WO2022171101A1 - 一种甾体偶联物 - Google Patents
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- WO2022171101A1 WO2022171101A1 PCT/CN2022/075589 CN2022075589W WO2022171101A1 WO 2022171101 A1 WO2022171101 A1 WO 2022171101A1 CN 2022075589 W CN2022075589 W CN 2022075589W WO 2022171101 A1 WO2022171101 A1 WO 2022171101A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
Definitions
- the present application relates to the field of biomedicine, in particular to a steroid conjugate.
- antibody-conjugated drugs and steroid compounds used for steroid conjugates can be used for the treatment of diseases or symptoms such as inflammation by acting on molecules such as glucocorticoid receptor signals.
- the current steroid-conjugated antibody-drug conjugates and steroids still have shortcomings in terms of efficacy and safety, so it is urgent to further develop a variety of steroid-formed antibody-drug conjugates and steroids to serve as A drug that can exert better efficacy and/or can have a better safety profile.
- the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , which may have one or more effects selected from the group consisting of: (1) the ability to affect immune cell activity; (2) targeting; (3) plasma stability; (4) biological safety (5) The ability to affect the release of cytokines from immune cells; (6) The ability to affect the transcription of IFN signaling pathway response genes; (7) The ability to affect the degree of skin fibrosis; (8) The ability to affect dendritic cells (9) the ability to affect skin collagen content; (10) the ability to affect GRE expression levels; (11) the ability to affect monocyte cytokine release; (12) the ability to affect exposure The ability to have sexual hypersensitivity; (13) the ability to affect skin swelling; and (14) the ability to affect arthritis symptoms.
- effects selected from the group consisting of: (1) the ability to affect immune cell activity; (2) targeting; (3) plasma stability; (4) biological safety (5) The ability to affect the release of
- the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof A useful salt, wherein the compound comprises the structure of formula (I-A):
- Tr I contains -(SP I-1 ) nI-1 -,
- Each SP I-1 is independently -N(R I-1c )-C(R I-1a )(R I-1b )-,
- R I-G1 and R I-G2 are each independently selected from the following group: hydrogen, halogen and alkyl, and R I-G3 is selected from the following group: O, S and N;
- nI-1 is at least 1.
- R I-G1 is hydrogen and R I-G2 is hydrogen.
- R I-G3 is O.
- nI-1 is 1.
- each R I-1a and R I-1b are each independently selected from the group consisting of hydrogen, alkyl, and alkyl substituted with at least one R I-2 .
- each R I-1a and R I-1b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-1a and R I-1b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- each R I-1c is each independently selected from the group consisting of hydrogen, alkyl, and alkyl substituted with at least one R I-2 .
- each R I-1c is each independently selected from the group consisting of hydrogen and alkyl.
- each R I-1c is each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- each R I-2 , R I-2a and R I-2b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-2 , R I-2a and R I-2b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- each SP I-1 is each independently selected from the group consisting of: -NH-CH2-, -NH-CH( CH3 )-, -NH-C( CH3 ) 2- , -N( CH3 ) -CH2- , -N( CH3 )-CH( CH3 )- and -N( CH3 )-C( CH3 ) 2- .
- each SP I-1 is each independently selected from the group consisting of: -NH-CH2-, -NH-CH( CH3 )-, -N( CH3 ) -CH2- , and -N( CH3 )-C( CH3 )-.
- Tr I further comprises -SP I-2- ,
- SP I-2 is -(C(R I-3a )(R I-3b )) nI-2 -,
- nI-2 is at least 0.
- nI-2 is selected from the group consisting of 0, 1, 2, and 3.
- each of R I-3a , R I-3b , and R I-3c are each independently selected from the group consisting of hydrogen and alkyl.
- each of R I-3a , R I-3b and R I-3c is each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
- each R I-4 , R I-4a and R I-4b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-4 , R I-4a and R I-4b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- SP I-2 is the residue of an amino acid.
- SP 1-2 is a residue selected from the group of amino acids: phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, Tyrosine, Alanine, Threonine, Histidine, Serine, Glutamine, Arginine, Lysine, Asparagine, Glutamic Acid, Proline, Citrulline, Cysteine , aspartic acid, glycine, valine, alanine and phenylalanine.
- amino acids phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, Tyrosine, Alanine, Threonine, Histidine, Serine, Glutamine, Arginine, Lysine, Asparagine, Glutamic Acid, Proline, Citrulline, Cysteine , aspartic acid, glycine, valine, alanine and phenylalanine.
- SP I-2 is a residue selected from the group of amino acids: glutamic acid, lysine, citrulline, glycine, and alanine.
- R Ip is selected from the group consisting of H, -CH 3 , -CH-(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-CH 2 -CH 3 , -CH 2 - C 6 H 5 , -C 8 NH 6 , -CH 2 -C 6 H 4 -OH, -CH 2 -COOH, -CH 2 -CONH 2 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 2 -S-CH 3 , -CH 2 -OH, -CH(CH 3 )-OH, -CH 2 -SH, -C 3 H6, -CH2 - C3H3N , -( CH2 ) 3 - NHC(NH) NH2 and -( CH2 ) 3 - NHCON
- R Ip is selected from the group consisting of H, -CH 3 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 and -(CH 2 ) 3 -NHCONH 2 .
- Tr I further comprises -(SP I-3 ) nI-3 -,
- nI-3 is at least 0.
- nI-3 is 1.
- each R I-5 , R I-5a and R I-5b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-5 , R I-5a and R I-5b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- Tr I further comprises -SP I-4- ,
- nI-4 and nI-5 are each independently at least 0.
- each of R I-6 , R I-7 and R I-8 are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-6 , R I-7 and R I-8 are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- Tr I comprises -SP I-2- (SP I-1 ) nI-1- .
- Tr I comprises -(SP I-3 ) nI-3 -SP I -2- (SP I-1 ) nI-1- .
- Tr I comprises -SP I-4- (SP I-3 ) nI-3 -SP I -2- (SP I-1 ) nI-1- .
- Tr I is selected from the following group:
- Tr I is selected from the following group:
- R I-1a , R I-1b , R I-1c and R I-3c is each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl
- R Ip is selected from the group consisting of H, -CH 3 , -CH-(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-CH 2 -CH 3 , -CH 2 - C 6 H 5 , -C 8 NH 6 , -CH 2 -C 6 H 4 -OH, -CH 2 -COOH, -CH 2 -CONH 2 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 2 -S-CH 3 , -CH 2 -OH, -CH(CH 3 )-OH, -CH 2 -SH, -C 3 H6, -CH2 - C3H3N , -( CH2 ) 3 - NHC(NH) NH2 and -( CH2 ) 3 - NHCON
- Tr I is selected from the following group:
- R Ip is selected from the group consisting of H, -CH 3 , -CH-(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-CH 2 -CH 3 , -CH 2 -C 6 H 5 , -C 8 NH 6 , -CH 2 -C 6 H 4 -OH, -CH 2 -COOH, -CH 2 -CONH 2 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 2 -S-CH 3 , -CH 2 -OH, -CH(CH 3 )-OH, -CH 2 -SH, - C3H6 , -CH2 - C3H3N , -( CH2 ) 3 -NHC(NH) NH2 and -( CH2 ) 3 -NH
- Tr I is selected from the following group:
- R Ip is selected from the group consisting of H, -CH 3 , -CH-(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-CH 2 -CH 3 , -CH 2 -C 6 H 5 , -C 8 NH 6 , -CH 2 -C 6 H 4 -OH, -CH 2 -COOH, -CH 2 -CONH 2 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 2 -S-CH 3 , -CH 2 -OH, -CH(CH 3 )-OH, -CH 2 -SH, - C3H6 , -CH2 - C3H3N , -( CH2 ) 3 -NHC(NH) NH2 and -( CH2 ) 3 -NH
- the compound comprises a structure selected from the group consisting of:
- R Ip is selected from the group consisting of H, -CH 3 , -CH-(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-CH 2 -CH 3 , -CH 2 -C 6 H 5 , -C 8 NH 6 , -CH 2 -C 6 H 4 -OH, -CH 2 -COOH, -CH 2 -CONH 2 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 2 -S-CH 3 , -CH 2 -OH, -CH(CH 3 )-OH, -CH 2 -SH, - C3H6 , -CH2 - C3H3N , -( CH2 ) 3 -NHC(NH) NH2 and -( CH2 ) 3 -NH
- Tr I is the Tr I described in any one of the application
- L I includes L I-1
- L I-1 is a divalent residue or a trivalent residue
- R I-G1 and R I-G2 are each independently is selected from the group consisting of hydrogen, halogen and alkyl
- R I-G3 is selected from the group consisting of O, S and N.
- R I-G1 is hydrogen and R I-G2 is hydrogen.
- R I-G3 is O.
- L I-1 is selected from the group consisting of: a divalent residue or trivalent residue formed by an amino group participating in the coupling, a divalent residue or a trivalent residue formed by a thiol group participating in the coupling, Bivalent or trivalent residues formed by coupling with click chemistry.
- L I-1 is selected from the group consisting of:
- L I-1 is selected from the group consisting of:
- R I-9 is selected from the group consisting of hydrogen and alkyl.
- R I-9 is selected from the group consisting of hydrogen and C1 - C6 alkyl.
- L I-1 is selected from the group consisting of:
- L I-1 is selected from the group consisting of:
- L I further comprises L I-2
- L I-2 is absent, or L I-2 comprises -X I- ,
- X I is -(C(R I-10a )(R I-10b )) pI-1 -,
- pi-1 is selected from the group consisting of 0, 1, 2, 3, 4, and 5.
- each R I-10a , R I-10b , and R I-10c are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-10a , R I-10b and R I-10c are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
- each of R I-11 , R I-11a and R I-11b are each independently selected from the group consisting of hydrogen and alkyl.
- each of R I-11 , R I-11a and R I-11b are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
- At least 1 methylene unit of X I is each independently replaced by a group selected from the group consisting of: -N(R I-10c )C(O)-, -C(O )N(R I-10c )-, -C(O)-, -OC(O)-, -C(O)O-, -NR I-10c- , -S- and -O-.
- 1 or 2 methylene units of X I are each independently replaced by a group selected from the group consisting of: -C(O)N(R I-10c )-, -S- , -C(O)-, -OC(O)-, -C(O)O-, and -NR I-10c- .
- R I-10a , R I-10b and R I-10c is independently selected from the group consisting of hydrogen and alkane base.
- X I is selected from the group consisting of -C(O)- and -C(O)-NH- CH2 -C( CH3 ) 2 -S-.
- L I-2 further comprises -B I- ,
- L Ip is a trivalent residue
- PEG I contains polyethylene glycol units
- pI-2 is at least 0.
- pi-2 is selected from the group consisting of 0, 1, 2, 3, 4, and 5.
- L Ip is selected from the group consisting of amino acids, amino alcohols, amino aldehydes and polyamines.
- L Ip is selected from the group consisting of aspartic acid, glutamic acid, histidine, lysine, arginine, serine, cysteine, threonine, and tyrosine acid.
- L Ip is selected from the group consisting of aspartic acid, glutamic acid and lysine.
- L Ip is:
- B Ip is selected from the group consisting of -NH-, -N( CH3 )-, -C(O)-, and -O-;
- pi-p is selected from the group: 0, 1, 2, 3, and 4.
- each R I-12a and R I-12b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-12a and R I-12b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- L Ip is selected from the following group:
- PEG I comprises -(PX I -(CH 2 CH 2 O) pi-3 ) pi-4 -, wherein pi-3 and pi-4 are each independently at least 1,
- PX I comprises -(C(R I-13a )(R I-13b )) pI-5 -
- pi-5 is selected from the group consisting of 0, 1, 2, 3, 4, and 5.
- each of R I-13a , R I-13b , and R I-13c are each independently selected from the group consisting of hydrogen and alkyl.
- each of R I-13a , R I-13b , and R I-13c are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- each R I-14 , R I-14a and R I-14b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-14 , R I-14a and R I-14b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- At least one methylene unit of PX I is each independently replaced by a group selected from the group consisting of: -N(R I-13c )C(O)-, -C(O )N(R I-13c )-, -C(O)-, -OC(O)-, -C(O)O-, -NR I-13c- , and -O-.
- 1 or 2 methylene units of PX I are each independently replaced with a group selected from the group consisting of: -C(O)-, -OC(O)-, -C( O) O-, and -NR I-13c- .
- PX I is selected from the group consisting of -C(O)- and -NR I-13c- .
- PX I is selected from the group consisting of -C(O)- and -NH-.
- pI-3 is selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, and 24.
- pi-3 is selected from the group consisting of 4, 6, 8, 10, 12 and 24.
- pi-3 is selected from the group consisting of 8, 9, 10, 12 and 24.
- pi-4 is selected from the group consisting of: 1, 2, 3, 4, and 5.
- PEG I further comprises -PZ I
- PZ I is selected from the group consisting of hydrogen, alkyl, and alkyl substituted with at least 1 R I-15 .
- PZ I is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyl substituted with at least 1 R I-15 .
- PZ I is selected from the group consisting of hydrogen, -CH2 - CH2 -C(O)OH, and methyl.
- PEG I is selected from the following group:
- B I is selected from the group consisting of:
- L I-2 further comprises -Y I- ,
- Y I is -(OCH 2 CH 2 ) pI-6 -O pI-7 -, and pI-6 and pI-7 are each independently at least 0.
- pi-7 is selected from the group: 0 and 1.
- pi-6 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
- pi-6 is selected from the group consisting of: 3, 4, 5, 6, 8, 10, and 12.
- pi-6 is selected from the group consisting of 3, 4, 5, 6, 7 and 8.
- pi-6 is selected from the group consisting of 3, 5 and 7.
- Y I is selected from the group consisting of -(OCH 2 CH 2 ) 3 -, -(OCH 2 CH 2 ) 4 -, -(OCH 2 CH 2 ) 5 -, -(OCH 2 CH 2 ) 6 -, -(OCH 2 CH 2 ) 7 - and -(OCH 2 CH 2 ) 8 -.
- Y I is selected from the group consisting of -(OCH 2 CH 2 ) 3 -, -(OCH 2 CH 2 ) 5 - and -(OCH 2 CH 2 ) 7 -.
- L I-2 further comprises -Z I- ,
- Z I is -(C(R I-16a )(R I-16b )) pI-8 -,
- pi-8 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7.
- each of R I-16a , R I-16b , and R I-16c are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-16a , R I-16b , and R I-16c are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- each R I-17 , R I-17a and R I-17b are each independently selected from the group consisting of hydrogen and alkyl.
- each R I-17 , R I-17a and R I-17b are each independently selected from the group consisting of hydrogen and C1 - C6 alkyl.
- At least one methylene unit of Z I is each independently replaced by a group selected from the group consisting of: -N(R I-16c )C(O)-, -C(O )N(R I-16c )-, -C(O)-, -OC(O)-, -C(O)O-, -NR I-16c- , and -O-.
- 1 or 2 methylene units of Z I are each independently replaced by a group selected from the group consisting of: -C(O)N(R I-16c )-, -C( O)-, -OC(O)-, -C(O)O-, and -NR I-16c- .
- Z I is selected from the group consisting of -NR I-16c- , -NR I-16c- (C(R I-16a )(R I-16b )) 2- , -(C (R I- 16a )(R I-16b )) 2 , -(C(R I-16a )(R I-16b )) 5 , -(C(R I-16a )(R I-16b )) 2 -C(O)-, -(C(R I-16a )(R I-16b )) 5 -C(O)-, -(C(R I- 16a )(R I-16b )) 2 -C (O)-NR I-16c -(C(R I-16a )(R I-16b )) 2 -, -(C(R I-16a )(R I-16b )) 2 -NR I-16c - C(O)-(C(R I-16a )(R I-16b )) 2
- Z I is selected from the group consisting of -NH-, -( CH2 ) 2- , -( CH2 ) 5- , ( CH2 ) 2 -C(O)-, -( CH 2 ) 4 -C(O)-, -(CH 2 ) 5 -C(O)-, -(CH 2 ) 2 -C(O)-NH-(CH 2 ) 2 -, -C(O) -( CH2 ) 2 -C(O)-NH-( CH2 ) 2- , -NH-( CH2 ) 2- and -CH2 -OC(O)-NH-( CH2 ) 2- .
- L I-2 comprises -Z I -X I- , -Z I- or -X I- .
- L I-2 comprises -Z I -X I -.
- L I-2 is selected from the group consisting of:
- L I-2 comprises -Z I -Y I -X I -, -Z I -Y I -, -Y I -X I - or -Y I -.
- L I-2 comprises -Z I -Y I -X I -.
- L I-2 is selected from the group consisting of:
- L I-2 comprises -Z I -B I -X I- , -Z I -B I- , -B I -X I- or -B I- .
- L I-2 comprises -Z I -B I- or -B I- .
- L I-2 is selected from the group consisting of:
- L I further comprises L I-3 , which is a polypeptide residue.
- L 1-3 comprises at least 1 amino acid residue.
- L 1-3 comprises a residue of a hydrophobic amino acid selected from the group consisting of phenylalanine (F), isoleucine (I), leucine (L), tryptophan (W), valine (V), methionine (M), tyrosine (Y), alanine (A), threonine (T), and histidine (H).
- phenylalanine F
- I isoleucine
- L leucine
- W tryptophan
- V valine
- M methionine
- Y tyrosine
- A alanine
- T threonine
- H histidine
- L 1-3 comprises a residue of a hydrophilic amino acid selected from the group consisting of serine (S), glutamine (Q), arginine (R), lysine (K) , asparagine (N), glutamic acid (E), proline (P), citrulline (C) and aspartic acid (D).
- S serine
- Q glutamine
- R arginine
- K lysine
- N glutamic acid
- E proline
- C citrulline
- D aspartic acid
- L 1-3 comprises glycine (G).
- L 1-3 does not comprise a residue of a hydrophilic amino acid.
- L 1-3 comprises a residue of an amino acid selected from the group consisting of glycine (G), valine (V), alanine (A) and phenylalanine (F).
- L 1-3 is selected from the group consisting of: Glycine-Glycine-Phenylalanine-Glycine (GGFG), Glycine-Glycine-Alanine-Glycine (GGAG), Alanine-Alanine Acid-Alanine-Glycine (AAAG), Glycine-Glycine-Glycine (GGGG), Glycine-Glycine-Alanine (GGA), Glycine-Alanine-Glycine (GAG), Glycine-Phenylalanine - Glycine (GFG), Valine-Alanine-Glycine (VAG), Alanine-Alanine-Glycine (AAG), Alanine-Alanine-Alanine (AAA), Valine - Alanine (VA), Alanine-Alanine (AA), Glycine-Alanine (GA), and Alanine-Glycine (AG).
- GFG Glycine-Glycine-Phenylalanine-Glycine
- GGAG Glycine-Glycine-Alanine
- LI -3 is selected from the group consisting of glycine-glycine-phenylalanine-glycine (GGFG) and alanine-alanine (AA).
- L 1-3 comprises at least 1 residue of a hydrophilic amino acid.
- L 1-3 comprises a residue of an amino acid selected from the group consisting of glycine (G), valine (V), alanine (A), citrulline (C), lysine amino acid (K), glutamic acid (E) and aspartic acid (D).
- G glycine
- V valine
- A alanine
- C citrulline
- K lysine amino acid
- K glutamic acid
- D aspartic acid
- L 1-3 is selected from the group consisting of: Glutamate-Alanine-Glycine-Glycine (EAGG), Glycine-Glutamate-Alanine-Glycine (GEAG), Glycine-Day Partic acid-alanine-glycine (GDAG), glycine-aspartic acid-glycine-glycine (GDGG), glycine-glutamic acid-glycine-glycine (GEGG), glutamic acid-glycine-glycine (EGG) , glutamic acid-alanine-glycine (EAG), aspartic acid-alanine-glycine (DAG), aspartic acid-glycine-glycine (DGG), valine-lysine-glycine ( VKG), glycine-aspartic acid-glycine (GDG), glycine-aspartic acid-alanine (GDA), glycine-glutamic acid-glycine (GEG), va
- L 1-3 is selected from the group consisting of glycine-glutamic acid-glycine (GEG), glutamic acid-alanine-glycine (EAG), glutamic acid-alanine (EA) ), glutamic acid-glycine (EG), and glycine-glutamic acid (GE).
- GAG glycine-glutamic acid-glycine
- EAG glutamic acid-alanine-glycine
- EA glutamic acid-alanine
- EG glutamic acid-glycine
- GE glycine-glutamic acid
- L 1-3 does not contain residues of hydrophobic amino acids.
- L 1-3 comprises a residue of an amino acid selected from the group consisting of glycine (G), glutamic acid (E) and aspartic acid (D).
- L 1-3 is selected from the group consisting of glycine-glutamic acid (GE), glycine-glycine (GG), aspartic acid-glycine (DG), glycine-aspartic acid (GD), glutamic acid-glycine (EG), glycine-aspartic acid-glycine (GDG), aspartic acid-glycine-glycine (DGG), glycine-glutamic acid-glycine (GEG), and glycine-day Partic acid-glycine-glycine (GDGG).
- L 1-3 is selected from the group consisting of glutamic acid-glycine (EG), glutamic acid-alanine (EA), glycine-glutamic acid (GE), valine- Citrulline (VC), Valine-Alanine (VA), Alanine-Alanine (AA), Glutamate-Alanine-Glycine (EAG), Glutamate-Glycine-Glycine ( EGG), Glycine-Glutamate-Glycine (GEG), Alanine-Alanine-Glycine (AAG), Alanine-Alanine-Alanine (AAA), Valine-Alanine- Glycine (VAG), Valine-Citrulline-Glycine (VCG), Valine-Lysine-Glycine (VKG), Glycine-Glycine-Phenylalanine-Glycine (GGFG), Glycine-Glycine-Glycine - glycine (GGGG), glycine-glutamic acid-glycine-g
- LI -3 is selected from the group consisting of alanine-alanine (AA), glutamic acid-alanine-glycine (EAG), glycine-glutamic acid-glycine (GEG) ), glutamic acid-alanine (EA), glutamic acid-glycine (EG), and glycine-glutamic acid (GE).
- AA alanine-alanine
- EAG glutamic acid-alanine-glycine
- GAG glycine-glutamic acid-glycine
- EA glutamic acid-alanine
- EG glutamic acid-glycine
- GE glycine-glutamic acid
- the present application provides a compound represented by formula (I-C) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
- Ab I is a ligand, and NaI is a number of at least 1;
- Tr I is the Tr I described in any one of the application, L I comprises L I-1 , and L I-1 is a divalent residue or a trivalent residue,
- R I-G1 and R I-G2 are each independently selected from the group consisting of hydrogen, halogen, and alkyl, and R I-G3 is selected from the group consisting of O, S, and N.
- R I-G3 is O.
- R I-G1 is hydrogen and R I-G2 is hydrogen.
- L I is the L I described in any one of the application.
- Ab I comprises an antibody or antigen-binding fragment thereof.
- the antibody is selected from the group consisting of murine antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies.
- the antigen-binding fragment is selected from the group consisting of Fab, Fab', Fv fragment, F(ab') 2 , F(ab) 2 , scFv, di-scFv, VHH and dAb.
- Ab I targets a target selected from the group consisting of:
- the present application provides a compound represented by formula (I-D) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
- Tr I is the Tr I described in any one of the application
- L Ix comprises L I-1x
- L I-1x is a linker
- R I-G1 and R I-G2 are each independently selected from the group consisting of hydrogen, halogen, and alkyl, and R I-G3 is selected from the group consisting of O, S, and N.
- R I-G3 is O.
- R I-G1 is hydrogen and R I-G2 is hydrogen.
- L I-1x is selected from the group consisting of groups capable of coupling to amino groups, groups capable of coupling to sulfhydryl groups, and click chemistry groups.
- L I-1x is selected from the following group:
- L I-1x is selected from the following group:
- each of R I-L1a , R I-L1b and R I-L1c is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, alkyl, alkenyl, alkynyl, alicyclic, heterocyclic, Aryl and Heteroaryl.
- L I-1x is selected from the following group:
- L Ix further comprises L I-2 , and L I-2 is the L I-2 described in any one of the application.
- L Ix further comprises L I-3 , and L I-3 is the L I-3 described in any one of the application.
- the present application provides a compound represented by formula (I-E) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
- Tr I is the Tr I described in any one of the application.
- R I-G1 and R I-G2 are each independently selected from the group consisting of hydrogen, halogen, and alkyl, and R I-G3 is selected from the group consisting of O, S, and N.
- R I-G3 is O.
- R I-G1 is hydrogen and R I-G2 is hydrogen.
- the compound comprises a structure selected from the group consisting of:
- R Ip is selected from the group consisting of H, -CH 3 , -CH-(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-CH 2 -CH 3 , -CH 2 -C 6 H 5 , -C 8 NH 6 , -CH 2 -C 6 H 4 -OH, -CH 2 -COOH, -CH 2 -CONH 2 , -(CH 2 ) 2 -COOH, -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 2 -S-CH 3 , -CH 2 -OH, -CH(CH 3 )-OH, -CH 2 -SH, - C3H6 , -CH2 - C3H3N , -( CH2 ) 3 -NHC(NH) NH2 and -( CH2 ) 3 -NH
- a method of affecting immune system function comprising administering to a subject a compound of any one of the present application or a tautomer, meso, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the present application.
- the affecting immune system function comprises affecting the function of immune cells.
- the immune cells are selected from the group consisting of granular leukocytes and agranular leukocytes.
- the immune cells are selected from the group consisting of neutrophils, eosinophils, and basophils.
- the immune cells are selected from the group consisting of lymphocytes and phagocytes.
- the immune cells are selected from the group consisting of B cells, T cells, natural killer cells, monocytes, macrophages, mast cells and dendritic cells.
- the disease and/or condition comprises a disease and/or condition associated with glucocorticoid receptor signaling.
- the disease and/or condition is selected from the group consisting of proliferative disease and/or condition, metabolic disease and/or condition, inflammatory disease and/or condition and neurodegenerative disease and/or symptoms.
- the disease and/or symptom is selected from the group consisting of: systemic autoimmune disease and/or symptom, blood system-related disease and/or symptom, neuromuscular system-related disease and/or Symptoms, digestive system-related diseases and/or symptoms, urinary system-related diseases and/or symptoms, endocrine gland system-related diseases and/or symptoms, skin-muscle system-related diseases and/or symptoms, and respiratory system-related diseases and/or symptoms .
- the disease and/or condition is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren's syndrome, ankylosing spondylitis, Wegener's granuloma edema and systemic sclerosis.
- the disease and/or condition is selected from the group consisting of autoimmune hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia and vasculitis .
- the disease and/or condition is selected from the group consisting of multiple sclerosis, myasthenia gravis and Gulumbarre syndrome.
- the disease and/or condition is selected from the group consisting of ulcerative colitis, Crohn's disease, autoimmune liver disease and atrophic gastritis.
- the disease and/or condition is selected from the group consisting of IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, pulmonary renal hemorrhage syndrome and lupus nephritis.
- the disease and/or condition is selected from the group consisting of type I diabetes, Grave's disease, Hashimoto's thyroiditis, primary adrenal atrophy and chronic thyroiditis.
- the disease and/or symptom is selected from the group consisting of psoriasis, astrospora vulgaris, cutaneous lupus erythematosus, dermatomyositis and polymyalgia rheumatica.
- the disease and/or condition is asthma.
- Figure 1 shows the results of inhibition of the release of IL-10 cytokines by ADC-I-743-1 of the present application.
- Figures 2A-2B show the results of inhibition of IL-1 ⁇ cytokine release by ADC-I-743-1 of the present application.
- Figure 3 shows the results of inhibition of the release of IL-10 cytokines by ADC-I-16-2 of the present application.
- Figure 4 shows the results of reducing ear swelling with the ADC of the present application.
- Figure 5 shows the results of the ADC of the present application reducing paw swelling in mice.
- Figures 6A and 6B show the results of the ADC of the present application inhibiting the release of cytokines from human peripheral blood mononuclear cells stimulated by R848.
- the term "ligand” generally refers to a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell.
- the role of the ligand can be to present the drug to the target cell population that binds to the ligand, including but not limited to protein hormones, lectins, growth factors, antibodies, or others that can bind to cells, receptors and/or antigens molecule.
- the ligand can be represented as Ab, and the ligand antigen forms a bond with the connecting unit through the heteroatom on the ligand, which can be an antibody or an antigen-binding fragment thereof, and the antibody can be selected from chimeric antibodies, human-derived antibody, fully human, or murine; the antibody may be a monoclonal antibody.
- the antibody may be an antibody or antigen-binding fragment thereof targeting the following targets: AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD163, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD46, CD47, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2, CD96, CLEC12A
- linker generally refers to a chemical structural fragment or bond that is connected to a ligand at one end and a drug at the other end. Other linkers can also be connected to the drug and/or the ligand.
- the direct or indirect linking of the ligand may refer to that the group is directly linked to the ligand through a covalent bond, or may be linked to the ligand through a linker.
- the linker can be a structure represented by Tr I or -(SPI -1 ) nI-1 - described in the present application.
- chemical fragments comprising acid-labile linker structures (eg, hydrazones), protease-sensitive (eg, peptidase-sensitive) linker structures, photolabile linker structures, dimethyl linker structures, or disulfide-containing linker structures can be used or bond as a linker.
- acid-labile linker structures eg, hydrazones
- protease-sensitive linker structures eg, peptidase-sensitive linker structures
- photolabile linker structures eg, dimethyl linker structures
- disulfide-containing linker structures can be used or bond as a linker.
- the term "optionally linked to other molecular moieties" of a structure generally means that the structure may not be linked to any other chemical structure, or that the structure may be linked to one or more other chemical structures than the structure.
- Other chemical structures eg, ligands described herein
- are linked eg, by chemical bonds, or by linkers).
- ligand-drug conjugate generally refers to the attachment of a ligand to a biologically active drug through a stable linking unit.
- ligand-drug conjugate may be an antibody-drug conjugate (antibody drug conjugate, ADC), and the ADC may refer to the combination of monoclonal antibodies or antibody fragments with biological Active drug linked.
- the drug can be an immunosuppressive drug.
- the drug may be ciclesonide (CAS number: 161115-59-9).
- antibody or antigen-binding fragment thereof generally refers to immunologically binding reagents and/or all antibodies from all species, including dimeric, trimeric and multimeric antibodies; bispecific Antibodies; Chimeric Antibodies; Fully Human Antibodies; Humanized Antibodies; Recombinant and Engineered Antibodies and Fragments thereof.
- the term "antibody or antigen-binding fragment thereof” may refer to any antibody-like molecule having an antigen-binding region, and the term includes fragments of small molecules such as Fab', Fab, F(ab') 2 , single domain antibodies (DABs), Fv , scFv (single chain Fv), linear antibodies, diabodies, etc.
- antigen-binding fragment can refer to one or more fragments of an antibody that retain the ability to specifically bind an antigen.
- fragments of full-length antibodies can be used for the antigen-binding function of antibodies. Techniques for making and using various antibody-based constructs and fragments are well known in the art.
- the antibody or antigen-binding fragment thereof may include an antibody or antigen-binding fragment thereof targeting the following targets: AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8 ,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CD11c,CD137,CD138,CD14,CD163,CD168,CD177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25 ,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,CD40,CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68,CD69,CD70 ,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90
- BDCA2 generally refers to a Type II C-type lectin.
- the BDCA2 of the present application may generally comprise Blood Dendritic Cells Antigen 2 (Blood Dendritic Cells Antigen 2), variants thereof, and functionally active fragments thereof.
- Targeting BDCA-2 can target the inflammatory environment of dendritic cells.
- the accession number for BDCA2 in UniProt may be Q8WTT0.
- TNF ⁇ generally refers to a cytokine, such as tumor necrosis factor- ⁇ .
- TNF ⁇ of the present application may generally comprise tumor necrosis factor- ⁇ , variants thereof, and functionally active fragments thereof.
- Targeting TNF ⁇ as a molecule can target the inflammatory environment.
- the accession number for TNF ⁇ in UniProt may be P01375.
- CD40 generally refers to a 50-55 kDa transmembrane glycoprotein of the tumor necrosis factor (TNF) receptor family.
- CD40 of the present application can generally comprise CD40, variants thereof, and functionally active fragments thereof.
- Targeting CD40 can target the inflammatory environment of B cells.
- the accession number for CD40 in UniProt may be A0A0S2Z3C7.
- IFNAR generally refers to the interferon receptor.
- the IFNARs of the present application may generally comprise interferon receptors, variants thereof, and functionally active fragments thereof.
- Targeting IFNAR molecules can target the inflammatory environment of immune cells.
- the UniProt accession number for IFNAR may be P17181.
- chimeric antibody generally refers to an antibody in which the variable region of a murine antibody is fused with the constant region of a human antibody, which can alleviate the immune response induced by the murine antibody.
- a hybridoma that secretes a mouse-specific monoclonal antibody can be established, and then the variable region gene can be cloned from the mouse hybridoma cell, and the constant region gene of the human antibody can be cloned according to the needs.
- the human constant region gene is connected into a chimeric gene and inserted into an expression vector, and the chimeric antibody molecule can be expressed in a eukaryotic system or a prokaryotic system.
- humanized antibody also known as CDR-grafted antibody
- CDR-grafted antibody generally refers to the grafting of murine CDR sequences into the framework of human antibody variable regions, i.e. different Types of human germline antibody framework sequences produced in antibodies.
- the heterologous reaction induced by chimeric antibodies can be overcome because they carry a large amount of murine protein components.
- framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
- the germline DNA sequences of the human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database.
- monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies.
- the antibodies or ligands described herein may be fully human monoclonal antibodies.
- Related technologies for the preparation of fully human antibodies include: human hybridoma technology, EBV transformation of B lymphocytes, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology.
- CDR generally refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contribute to antigen binding.
- 6 CDRs are provided by Kabat E.A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242), Chothia et al., “CanonicalStructures For the Hypervariable Regions of Immunoglobulins," J. Mol. Biol. 196:901 (1987); and MacCallum et al., “Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography,” J. Mol. Biol. 262:732 (1996)).
- CDR L1, CDR L2, CDR L3 or L1, L2, L3 the Kabat definition of CDRs can be applied to CDR1, CDR2 and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domains, as well as the heavy chain variable domains of CDR1, CDR2 and CDR3 (CDR H1, CDR H2, CDR H3 or H1, H2, H3).
- methylene generally refers to a residue derived from a group of 1 carbon atom by removing two hydrogen atoms. Methylene groups can be substituted or unsubstituted, substituted or unsubstituted.
- alkylene generally refers to a saturated straight or branched aliphatic hydrocarbon group having 2 residues derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane, which It may be a straight or branched chain group containing from 1 to 20 carbon atoms, eg, an alkylene group containing from 1 to 12 carbon atoms, eg, containing from 1 to 6 carbon atoms.
- Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene ( -CH2CH2CH2- ), 1,4 - Butylene ( -CH2CH2CH2CH2- ) and 1,5 - Butylene ( -CH2CH2CH2CH2CH2- ) Wait.
- Alkylene may be substituted or unsubstituted, substituted or non-substituted, for example, when substituted, substituents may be substituted at any available point of attachment, which may be independently optionally selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy substituted by one or more substituents in the group, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O)
- aryl generally refers to residues having an aromatic ring derived by removing one hydrogen atom.
- aromatic ring may refer to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (ie, rings that share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and may be 6 to 10 membered, such as benzene and Naphthalene.
- the aromatic ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring.
- Aryl may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , and heterocycloalkylthio.
- Aryl groups can be substituted or unsubstituted.
- heteroaryl generally refers to a residue having a hydrogen atom removed from a carbon atom of a heteroaromatic ring.
- heteromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen.
- Heteroaryl can be 5 to 10 membered, 5 membered or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazole Base et al.
- the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
- Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy group, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, and heterocycloalkylthio. Heteroaryl groups can be substituted or unsubstituted.
- heterocyclyl generally refers to stable non-aromatic 3- to 7-membered monocyclic carbocyclic structures, fused 7- to 10-membered bicyclic heterocyclic structures or bridged 6-membered- 10-membered bicyclic heterocyclic structures, these cyclic structures can be saturated or partially saturated, in addition to carbon atoms, these cyclic structures also contain one or more heteroatoms, wherein the heteroatoms can be selected from the following Groups: Oxygen, Sulfur and Nitrogen. For example, it contains 1-4 heteroatoms as defined above. When used to refer to an atom on a heterocyclic ring structure, the term “nitrogen” may include nitrogen that has undergone a substitution reaction. Heterocyclyl groups can be substituted or unsubstituted. Heterocyclylene groups can be substituted or unsubstituted.
- heterocycloalkyl generally refers to stable non-aromatic 3- to 7-membered monocycloalkane structures, fused 7- to 10-membered bicyclic heterocyclic structures or bridged 6-membered- 10-membered bicyclic heterocyclic structures containing, in addition to carbon atoms, one or more heteroatoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
- nitrogen may include nitrogen that has undergone a substitution reaction.
- Heterocycloalkyl can be substituted or unsubstituted.
- alicyclic group generally refers to a residue having a hydrogen atom removed from the same carbon atom or a plurality of different carbon atoms of an alicyclic ring.
- cycloalkane generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocyclic ring containing 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
- Non-limiting examples of alicyclic groups include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc.; polycyclic carbocycles may include spiro, fused, and bridged carbocycles. Alicyclic groups can be substituted or unsubstituted.
- the term "carbocyclyl" generally refers to a residue derived from a carbon atom having a carbocyclic ring by removing one hydrogen atom.
- carbocycle generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocycle contains 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
- Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Carbocyclyl groups can be substituted or unsubstituted. Alicyclic and carbocyclic may be used interchangeably in some cases.
- partially unsaturated generally refers to a cyclic structure containing at least one double or triple bond between the ring molecules.
- the term “partially unsaturated” encompasses cyclic structures with multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined herein.
- the term “unsaturated” means that the moiety has one or more degrees of unsaturation.
- halogen generally refers to fluorine, chlorine, bromine, iodine, and may be, for example, fluorine, chlorine.
- aliphatic group generally refers to straight-chain, branched or cyclic hydrocarbons having 1 to 12 carbon atoms, either fully saturated; or with one or Multiple unsaturated units, but the unsaturated units are not aromatic groups.
- suitable aliphatic groups may include substituted or unsubstituted linear, branched or cyclic structures of alkyl, alkenyl, alkynyl, and mixtures of these groups; such as (cycloalkyl)alkyl , (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
- aliphatic groups have 1-12, 1-8, 1-6, 1-4, or 1-3 carbon atoms. Aliphatic groups can be substituted or unsubstituted.
- alkyl generally refers to a residue derived from an alkane by removal of a hydrogen atom. Alkyl groups can be substituted or unsubstituted, substituted or unsubstituted.
- alkyl generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having a residue derived by removing a hydrogen atom from the same carbon atom or two different carbon atoms of the parent alkane, which may be a group containing 1 to A straight or branched chain group of 20 carbon atoms, eg 1 to 12 carbon atoms, eg, an alkane alkyl group containing 1 to 6 carbon atoms.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like.
- Alkyl groups may be substituted or unsubstituted, substituted or non-substituted, for example when substituted, substituents may be substituted at any available point of attachment, and the substituents may be independently optionally selected from alkyl groups , alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and one or more substituents in oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , - CN, -OH,
- alkenyl generally refers to a straight or branched chain hydrocarbon group containing one or more double bonds.
- alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, and hexenyl.
- C2-6 alkenyl groups having more than one double bond include butadienyl, pentadienyl, hexadienyl, and hexatrienyl and branched forms thereof.
- the position of the unsaturated bond (double bond) can be anywhere in the carbon chain.
- Alkenyl groups can be substituted or unsubstituted.
- alkynyl generally refers to unsaturated straight or branched chain alkynyl groups such as ethynyl, 1-propynyl, propargyl, butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
- trivalent group or “trivalent residue” generally refers to a group having 3 bonding positions in the group.
- trivalent groups include, but are not limited to, trivalent alkane groups, trivalent cycloalkyl groups, trivalent heterocycloalkyl groups, trivalent alkenyl groups, trivalent alkynyl groups, trivalent aryl groups, Trivalent heteroaryl groups and trivalent linkers in this application.
- divalent group or divalent residue generally refers to a group having 2 bonding positions in the group.
- divalent groups include, but are not limited to, divalent alkane groups, divalent cycloalkyl groups, divalent heterocycloalkyl groups, divalent alkenyl groups, divalent alkynyl groups, divalent aryl groups, Divalent heteroaryl groups and divalent linkers in this application.
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification may include both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group. situation.
- group capable of coupling with an amino group generally means that the compound A has an amino group, the compound B has a group capable of coupling with an amino group, and the compound B has a group capable of coupling with an amino group through a group capable of coupling with an amino group.
- the group reacts with the amino group of compound A, which can realize the connection between compound A and compound B.
- group capable of coupling with a thiol group generally means that the compound A has a thiol group, the compound B has a group capable of coupling with a thiol group, and the compound B has a group capable of coupling with a thiol group through a group capable of coupling with a thiol group.
- the group reacts with the sulfhydryl group of compound A, which can realize the connection between compound A and compound B.
- click chemistry group generally refers to a reactive group capable of fast and efficient coupling.
- click chemistry reactions can include the following groups of reactions: cycloaddition reactions, nucleophilic ring-opening reactions, non-aldol carbonyl chemistry, and addition reactions of carbon-carbon multiple bonds.
- a click chemistry group can be selected from the following group:
- the "attachment" of a group X to a group Y can generally be in any orientation, and any orientation generally means that when the group X is used to link the Y and the group Z, the group X's Two or more attachment sites can optionally be attached to the group Y or the group Z.
- -C(O)O- of SP 2 is linked to -NH-CH 2 - of (SP 1 ) n1 , which can be the C atom of SP 2 linked to the N atom of (SP 1 ) n1 , which can be SP 2
- the O atom is connected to the N atom of (SP 1 ) n1
- the C atom of SP 2 may be connected to the atom of (SP 1 ) n1
- the O atom of SP 2 may be connected to the C atom of (SP 1 ) n1 .
- substituted generally means that one or more hydrogen atoms in a group, eg up to 5, eg 1 to 3 hydrogen atoms, independently of one another, are substituted with the corresponding number of substituents.
- Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
- amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
- the term 0 or more (eg, 0 or more, 0 or 1, 0) methylene units "replaced” generally refers to when the structure contains 1 or more
- One or more hydrogen atoms in the group are substituted by the corresponding number of substituents.
- Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
- amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
- the term "compound” generally refers to a substance having two or more different elements.
- the compound of the present application may be an organic compound.
- the compound of the present application may be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1,000 or less, or a compound with a molecular weight of 1,000 or more, or a compound of 10,000 or more and 100,000 or more. compound.
- a compound may also refer to a compound connected by chemical bonds, for example, it may be a compound in which one or more molecules with a molecular weight below 1000 are connected with a biological macromolecule by chemical bonds, and the biological macromolecule may be a high polysaccharide, a protein , nucleic acids, peptides, etc.
- the compounds of the present application can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 1000, can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 10,000, and can include proteins and one or more molecular weights. Compounds with less than 100,000 molecules linked together.
- structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms.
- the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by carbon 13 or 1 carbon 14, the compounds whose structure is consistent with the present application are all within the scope of the present application.
- hydrophilic amino acid usually refers to the hydrophilicity of glycine as a standard, and amino acids with higher hydrophilicity than glycine can be used as hydrophilic amino acids.
- the hydrophilic amino acid may comprise an amino acid selected from the group consisting of serine (S), glutamine (Q), arginine (R), lysine (K), asparagine (N), glutamic acid (E), proline (P), and aspartic acid (D).
- hydrophobic amino acid generally refers to the hydrophilicity of glycine as a standard, and amino acids whose hydrophilicity is lower than that of glycine can be regarded as hydrophobic amino acids.
- the hydrophobic amino acid may comprise an amino acid selected from the group consisting of phenylalanine (F), isoleucine (I), leucine (L), tryptophan (W), valine (V), Methionine (M), Tyrosine (Y), Citrulline (C), Alanine (A), Threonine (T), and Histidine (H).
- phenylalanine F
- isoleucine I
- leucine L
- tryptophan W
- valine V
- Methionine M
- Tyrosine Y
- Citrulline C
- Alanine (A) Threonine
- T Threonine
- H Histidine
- glycine as a special amino acid, is neither a hydrophilic nor a hydrophobic amino acid.
- the term "pharmaceutical composition” generally refers to a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other Such as physiological/pharmaceutically acceptable carriers and excipients.
- the pharmaceutical composition can facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- the preparation of conventional pharmaceutical compositions can be found in the Chinese Pharmacopoeia.
- the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” generally refers to a salt of a compound or ligand-drug conjugate of the present application, or a salt of a compound described in the present application, which Such salts can be safe and/or effective when used in mammals, and can have due biological activity.
- the antibody-antibody drug conjugate compounds of the present application can form salts with acids, non-pharmaceutically acceptable salts.
- Limiting examples include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, pearic acid Salt, hydrogen phosphate, dihydrogen phosphate, salicylates, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate acid salt, benzene sulfonate, p-toluene sulfonate.
- solvate generally refers to the ligand-drug conjugate compound of the present application forming a pharmaceutically acceptable solvate with one or more solvent molecules, non-limiting solvent molecules
- solvent molecules non-limiting solvent molecules
- examples include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate, DMA, DMF, methanol, propanol, glycerol, ethylene glycol, tert-butanol, dioxane, tetrahydrofuran.
- drug loading usually refers to the average amount of drug loaded on each ligand, and can also be expressed as the ratio of drug and antibody amounts. Drug loading can range from 0-12 per ligand (Ab) linked , eg 1-10 drugs. In the embodiment of the present application, the drug loading is expressed as Na , which can be the mean value of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 exemplarily.
- the drug loading of each ADC molecule after conjugation reaction can be characterized by conventional methods such as UV/Vis spectroscopy, mass spectrometry, ELISA assay and HPLC. For example, the number of chemical bonds connecting the ligand in the present application may not be limited to one.
- the horizontal line can indicate that the ligand is connected to the drug or the ligand is connected to the linker
- the horizontal line can indicate that the ligand is connected to the drug or
- the linker is connected by one chemical bond, such as covalent bond, or it can also mean that the ligand and the drug or the linker are connected by two or more chemical bonds, such as covalent bond.
- the pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- sterile fixed oils are conveniently employed as a solvent or suspending medium.
- any blended fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid can also be used in the preparation of injectables.
- the term "about” generally refers to a range of 0.5%-10% above or below the specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.
- the compounds of the present application include tautomers, mesomers, racemates, enantiomers, and/or diastereomers of the compounds.
- the term “diastereomer” generally refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, eg, melting points, boiling points, spectral properties, and reactivities.
- the terms “tautomer” or “tautomeric form” are used interchangeably and generally refer to structural isomers of different energies that can be interconverted through a low energy barrier.
- protontautomers also known as prototropic tautomers
- prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence tautomers include interconversions by recombination of some of the bonding electrons.
- mesome generally refers to atoms that contain asymmetry in the molecule, but have a symmetry factor such that the total optical rotation in the molecule is zero.
- racemate or “racemic mixture” refers to a composition consisting of two enantiomeric species in equimolar amounts.
- certain atoms of the compounds of the present application may occur in more than one isotopic form.
- hydrogen may exist as protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), and carbon may exist naturally in three different isotopes ( 12 C, 13 C, and 14 C).
- isotopes that can be incorporated into the compounds of the present application also include, but are not limited to, 15 N, 18 O, 17 O, 18 F, 32 P, 33 P, 129 I, 131 I, 123 I, 124 I, 125 I, or the like of isotopes.
- the compounds of the present application may be enriched in one or more of these isotopes relative to their natural abundance.
- Such isotopically enriched compounds can be used for a variety of purposes, as known to those skilled in the art.
- substitution with heavy isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages, which may be due to greater metabolic stability.
- the natural abundance of deuterium ( 2 H) is about 0.015%. Therefore, for every 6,500 hydrogen atoms in nature, there is one deuterium atom. Accordingly, the deuterium-containing compounds of the present invention have a deuterium abundance greater than 0.015% at one or more positions (as the case may be).
- the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise the following structures in Table 1:
- NaI represents the average number of drugs loaded by the compounds in the list, for example, NaI can be any number greater than 0, where Ab represents the ligand part of the compounds in the list, and Ab can be any of the ligands represented in this application. body.
- the ligands described herein may be protein hormones, lectins, growth factors, antibodies, or other molecules capable of binding to cells, receptors and/or antigens.
- the ligands of the present application can be antibodies or antigen-binding fragments thereof.
- the ligand comprises at least one CDR in the variable region VL of the antibody light chain.
- the CDRs described in the present application may be defined according to Kabat; or may be defined according to Chothia, and the CDR sequences defined in various ways are all included within the protection scope of the present application.
- the antigen binding protein may comprise LCDR1, and the LCDR1 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 21 and 31.
- the CDRs may be defined according to Kabat.
- the antigen binding protein may comprise LCDR2, and the LCDR2 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 3-4, 22 and 32.
- the CDRs may be defined according to Kabat.
- the antigen binding protein may comprise LCDR3, and the LCDR3 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 23 and 33.
- the CDRs may be defined according to Kabat.
- the isolated antigen binding protein may comprise LCDR1-3.
- the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 21 and 31;
- the LCDR2 comprises the amino acid shown in any one of SEQ ID NOs: 3-4, 22 and 32 and the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NOs: 5-6, 23 and 33.
- the CDRs may be defined according to Kabat.
- the antigen binding protein described in the present application can comprise the same LCDR1-3 as BIIB059, wherein, the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO: 1; the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO: 3 and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:5.
- the antigen binding proteins described herein may have BDCA2 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen binding protein described in the present application can comprise the same LCDR1-3 as Humira, wherein, the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO:2; the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO:4 and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:6.
- the antigen binding proteins described herein may have TNF ⁇ binding ability.
- the CDRs may be defined according to Kabat.
- the antigen-binding protein described in the present application can comprise the same LCDR1-3 as Iscalimab, wherein the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO: 21; the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO: 22 and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 23.
- the antigen binding proteins described herein may have CD40 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen binding protein described in the present application can comprise the same LCDR1-3 as Anifrolumab, wherein the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO:31; the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO:32 and the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:33.
- the antigen binding proteins described herein may have IFNAR binding ability.
- the antigen binding proteins described herein may have IFNAR1 binding ability.
- the CDRs may be defined according to Kabat.
- Antigen-binding proteins described herein may comprise at least one CDR in the VH of an antibody heavy chain variable region.
- the CDRs may be defined according to Kabat.
- the antigen binding protein may comprise HCDR1, and the HCDR1 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 7-8, 24 and 34.
- the CDRs may be defined according to Kabat.
- the antigen binding protein may comprise HCDR2, and the HCDR2 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 9-10, 25 and 35.
- the CDRs may be defined according to Kabat.
- the antigen binding protein may comprise HCDR3, and the HCDR3 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 11-12, 26 and 36.
- the CDRs may be defined according to Kabat.
- the isolated antigen binding protein may comprise HCDR1-3.
- the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NOs: 7-8, 24 and 34;
- the HCDR2 comprises the amino acid shown in any one of SEQ ID NOs: 9-10, 25 and 35 and
- the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NOs: 11-12, 26 and 36.
- the CDRs may be defined according to Kabat.
- the antigen-binding protein described in the present application may comprise the same HCDR1-3 as BIIB059, wherein the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:7; the HCDR2 may comprise the amino acid sequence shown in SEQ ID NO:9 and the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 11.
- the antigen binding proteins described herein may have BDCA2 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen-binding protein described in the present application may comprise the same HCDR1-3 as Humira, wherein the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:8; the HCDR2 may comprise the amino acid sequence shown in SEQ ID NO:10 and the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 12.
- the antigen binding proteins described herein may have TNF ⁇ binding ability.
- the CDRs may be defined according to Kabat.
- the antigen-binding protein described in the present application may comprise the same HCDR1-3 as Iscalimab, wherein the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:24; the HCDR2 may comprise the amino acid sequence shown in SEQ ID NO:25 and the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 26.
- the antigen binding proteins described herein may have CD40 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen binding protein described in the present application may comprise the same HCDR1-3 as Anifrolumab, wherein the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:34; the HCDR2 may comprise the amino acid sequence shown in SEQ ID NO:35 and the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO:36.
- the antigen binding proteins described herein may have IFNAR binding ability.
- the antigen binding proteins described herein may have IFNAR1 binding ability.
- the CDRs may be defined according to Kabat.
- the isolated antigen binding protein may comprise LCDR1-3 and HCDR1-3.
- the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NOs: 1-2, 21 and 31;
- the LCDR2 comprises the amino acid shown in any one of SEQ ID NOs: 3-4, 22 and 32 Sequence;
- the LCDR3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 5-6, 23 and 33;
- the HCDR1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 7-8, 24 and 34 sequence;
- the HCDR2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9-10, 25 and 35;
- the HCDR3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11-12, 26 and 36 amino acid sequence.
- the CDRs may be defined according to Kabat.
- the antigen binding proteins described herein may comprise the same LCDR1-3 and HCDR1-3 as BIIB059.
- the antigen binding proteins described herein may have BDCA2 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen binding proteins described herein may comprise the same LCDR1-3 and HCDR1-3 as Humira.
- the LCDR1 may comprise the amino acid sequence shown in SEQ ID NO:2; the LCDR2 may comprise the amino acid sequence shown in SEQ ID NO:4; the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:6;
- the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:8; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:10; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:12.
- the antigen binding proteins described herein may have TNF ⁇ binding ability.
- the CDRs may be defined according to Kabat.
- the antigen-binding protein described in the present application can comprise the same LCDR1-3 as Iscalimab, wherein the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO: 21; the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO: 22
- the LCDR3 may comprise the amino acid sequence shown in SEQ ID NO: 23; the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO: 24; the HCDR2 may comprise the amino acid sequence shown in SEQ ID NO: 25 and the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO:26.
- the antigen binding proteins described herein may have CD40 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen binding protein described in the present application can comprise the same LCDR1-3 as Anifrolumab, wherein the LCDR1 can comprise the amino acid sequence shown in SEQ ID NO:31; the LCDR2 can comprise the amino acid sequence shown in SEQ ID NO:32
- the amino acid sequence of the LCDR3 can include the amino acid sequence shown in SEQ ID NO: 33; the HCDR1 can include the amino acid sequence shown in SEQ ID NO: 34; the HCDR2 can include the amino acid sequence shown in SEQ ID NO: 35 and the HCDR3 may comprise the amino acid sequence shown in SEQ ID NO:36.
- the antigen binding proteins described herein may have IFNAR binding ability.
- the antigen binding proteins described herein may have IFNAR1 binding ability.
- the CDRs may be defined according to Kabat.
- the antigen binding protein may comprise a light chain variable region VL, and the VL may comprise the amino acid sequence shown in any one of SEQ ID NOs: 13-14, 28 and 38.
- the antigen binding protein may comprise a heavy chain variable region VH, and the VH may comprise the amino acid sequence shown in any one of SEQ ID NOs: 15-16, 27 and 37.
- the antigen binding protein may comprise a light chain variable region VL and a heavy chain variable region VH.
- the VL may comprise the amino acid sequence shown in any one of SEQ ID NOs: 13-14, 28 and 38
- the VH may comprise the amino acid sequence shown in any one of SEQ ID NOs: 15-16, 27 and 37 amino acid sequence shown.
- the antigen binding proteins described herein may comprise the same light chain variable region VL and heavy chain variable region VH as BIIB059.
- the VL may comprise the amino acid sequence shown in SEQ ID NO: 13
- the VH may comprise the amino acid sequence shown in SEQ ID NO: 15.
- the antigen binding proteins described herein may have BDCA2 binding ability.
- the antigen binding proteins described herein may comprise the same light chain variable region VL and heavy chain variable region VH as Humira.
- the VL may comprise the amino acid sequence shown in SEQ ID NO: 14
- the VH may comprise the amino acid sequence shown in SEQ ID NO: 16.
- the antigen binding proteins described herein may have TNF ⁇ binding ability.
- the antigen binding proteins described herein may comprise the same light chain variable region VL and heavy chain variable region VH as Iscalimab.
- the VL may comprise the amino acid sequence shown in SEQ ID NO: 28
- the VH may comprise the amino acid sequence shown in SEQ ID NO: 27.
- the antigen binding proteins described herein may have CD40 binding ability.
- the antigen binding proteins described herein may comprise the same light chain variable region VL and heavy chain variable region VH as Anifrolumab.
- the VL may comprise the amino acid sequence shown in SEQ ID NO:38
- the VH may comprise the amino acid sequence shown in SEQ ID NO:37.
- the antigen binding proteins described herein may have IFNAR binding ability.
- the antigen binding proteins described herein may have IFNAR1 binding ability.
- the antigen binding protein may comprise a light chain, and the light chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 17-18, 29 and 39.
- the antigen binding protein may comprise a heavy chain, and the heavy chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 19-20, 30 and 40.
- the antigen-binding protein may comprise an antibody light chain and an antibody heavy chain, wherein the light chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 17-18, 29 and 39, and the The heavy chain may comprise the amino acid sequence set forth in any one of SEQ ID NOs: 19-20, 30 and 40.
- the antigen-binding protein described herein may comprise the same antibody light chain and antibody heavy chain as BIIB059, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 17, and the heavy chain may comprise The amino acid sequence shown in SEQ ID NO:19.
- the antigen binding proteins described herein may have BDCA2 binding ability.
- the antigen binding protein described herein may comprise the same antibody light chain and antibody heavy chain as Humira, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 18, and the heavy chain may comprise The amino acid sequence shown in SEQ ID NO:20.
- the antigen binding proteins described herein may have TNF ⁇ binding ability.
- the antigen binding protein described herein may comprise the same antibody light chain and antibody heavy chain as Iscalimab, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 29, and the heavy chain may comprise The amino acid sequence shown in SEQ ID NO:30.
- the antigen binding proteins described herein may have CD40 binding ability.
- the antigen binding protein described herein may comprise the same antibody light chain and antibody heavy chain as Anifrolumab, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 39, and the heavy chain may comprise The amino acid sequence shown in SEQ ID NO:40.
- the antigen-binding protein described in the present application may have IFNAR (interferon- ⁇ / ⁇ receptor) binding ability.
- the antigen-binding protein described in this application may have IFNAR1 (interferon- ⁇ / ⁇ receptor 1) binding ability.
- the first step the compound of general formula (Y1) and the compound of general formula (Y2) are reacted under optional basic conditions to obtain general formula (Y3);
- the second step the compound of general formula (P1) and the compound of general formula (Y4) are optionally reacted under acidic or basic conditions to obtain general formula (P2);
- the third step the compound of general formula (P2) removes the protecting group PG to obtain general formula (P3);
- the third step the compound of general formula (P3) and the compound of general formula (Y3) are optionally reacted under basic conditions in the presence of an optional condensing agent to obtain a compound represented by formula (I-D);
- AG 1 and AG 2 are commonly used hydroxyl or amino activating groups
- PG is the protecting group of common hydroxyl, amino or carboxyl
- L 3 a and L 3 b can jointly form L I - 3 or L II-3 respectively defined by any compound represented by formula (ID) or formula (II-D) in the present application; Tr, L 1x , L 2 , and L 3 can be respectively as defined in Tr I , L I-1x , L I- 2 , L I-3 in the compound represented by any formula (ID) of the present application, or as defined in any of the formula (II-D) of the present application In the compounds shown, Tr II , L II-1x , L II-2 , L II-3 are defined;
- Reagents providing basic conditions include organic bases and inorganic bases
- the organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.
- the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, hydroxide Sodium, lithium hydroxide, etc.
- Reagents that provide acidic conditions include protic acids and Lewis acids, including but not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, Benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; the Lewis acids include but are not limited to boron trifluoride, zinc chloride, magnesium chloride, chlorine Aluminum, Tin Chloride, Ferric Chloride;
- the condensing agent may be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, 1-hydroxybenzotriazole and 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide , 0-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole , 0-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N' - tetramethylurea hexafluorophosphate, benzotriazol-1-yl
- the first step the compound of general formula (Y1) and the compound of general formula (Y2) are reacted under optional basic conditions to obtain general formula (Y3);
- the second step the compound of general formula (P1) and the compound of general formula (Y4) are optionally reacted under acidic or basic conditions to obtain general formula (P2);
- the third step the compound of general formula (P2) removes the protecting group PG 2 to obtain general formula (P3);
- the third step the compound of general formula (P3) and the compound of general formula (Y3) are optionally reacted under basic conditions in the presence of an optional condensing agent to obtain general formula (P4);
- the fourth step removing the protecting group PG 1 from the compound of the general formula (P4) to obtain the compound represented by the formula (ID);
- AG 1 and AG 2 are commonly used activating groups of hydroxyl, or amino or other groups
- PG 1 and PG 2 are protective groups for any amino group, carboxyl group or hydroxyl group;
- L 3 a and L 3 b can jointly form L I - 3 or L II-3 respectively defined by any compound represented by formula (ID) or formula (II-D) in the present application; Tr, L 1x , L 2 , L 3 can be respectively as defined in Tr I , L I-1x , L I-2 , L I-3 in the compound represented by any formula (ID) of the present application, or as represented by any formula (II-D) of the present application Tr II , L II-1x , L II-2 , L II-3 are defined in the compound of ;
- Reagents providing basic conditions include organic bases and inorganic bases
- the organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.
- the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, hydroxide Sodium, lithium hydroxide, etc.
- Reagents that provide acidic conditions include protic acids and Lewis acids, including but not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, Benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; the Lewis acids include but are not limited to boron trifluoride, zinc chloride, magnesium chloride, chlorine Aluminum, Tin Chloride, Ferric Chloride;
- the condensing agent may be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, 1-hydroxybenzotriazole and 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide , 0-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole , 0-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N' - tetramethylurea hexafluorophosphate, benzotriazol-1-yl
- the first step the compound of general formula (P1) and the activating reagent are optionally reacted under acidic or basic conditions to obtain general formula (P2);
- the third step the compound of general formula (P3) removes the protecting group PG1 to obtain general formula (P4);
- the fourth step the compound of general formula (P4) and the compound of general formula (Y2) are optionally reacted under acidic or basic conditions to obtain general formula (P5);
- the 5th step the compound of general formula (P4) removes protecting group PG2, obtains general formula (P6);
- the sixth step the compound of general formula (P6) and the compound of general formula (Y3) are optionally reacted under acidic or basic conditions to obtain the compound shown in formula (I-D);
- AG is the activating group of commonly used hydroxyl, or amino or other groups
- PG 1 and PG 2 are protective groups for any amino group, carboxyl group or hydroxyl group;
- SP 1 , SP 2 and SP 3 can jointly form Tr I or Tr II defined by any compound represented by formula (ID) or formula (II-D) in the present application;
- L 1x , L 2 , L 3 can be respectively as follows L I-1x , L I-2 , L I - 3 in the compound represented by any formula (ID) in the present application are as defined, or in the compound represented by any formula (II-D) in the present application, L II-1x , As defined by L II-2 and L II-3 ;
- SP 1 , SP 2 and SP 3 can also be respectively as SP I-1 , SP I-2 and SP I-3 in the compound represented by any formula (IA) of the present application As defined, or as defined in SP II-1 , SP II-2 , SP II-3 in any compound represented by formula (II-A) of this application;
- Reagents providing basic conditions include organic bases and inorganic bases
- the organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.
- the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, hydroxide Sodium, lithium hydroxide, etc.
- Reagents that provide acidic conditions include protic acids and Lewis acids, including but not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, Benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; the Lewis acids include but are not limited to boron trifluoride, zinc chloride, magnesium chloride, chlorine Aluminum, Tin Chloride, Ferric Chloride;
- the condensing agent may be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, 1-hydroxybenzotriazole and 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide , 0-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole , 0-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N' - tetramethylurea hexafluorophosphate, benzotriazol-1-yl
- Ligand Ab reacts with any compound represented by formula (I-D) or formula (II-D) of this application in an acidic, neutral or basic buffer to obtain formula (I-C) or formula (II-C) compound of;
- Ab is a ligand containing at least one free sulfhydryl group (-SH), wherein the free sulfhydryl group can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl) phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, the disulfide bond (-S-S-) between the ligand chains can be reduced to form a free thiol group;
- Tr, L 2 and L 3 can be respectively as defined in Tr I , L I-2 and L I-3 in the compound represented by any formula (ID) of the present application, or as represented by any formula (II-D) of the present application Tr II , L II-2 and L II -3 in the compound of In the compound represented by the formula (II-C), Ab II and Na -II are defined;
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, diphosphate dibasic Potassium hydrogen-dipotassium phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine - HCl buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, ammonia water-ammonium chloride Buffer, sodium barbital-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium
- the ligand Ab reacts with any compound represented by formula (I-D) or formula (II-D) of the present application in an acidic, neutral or basic buffer to obtain formula (I-C) or formula (II- C) the compound shown;
- Ab is a ligand containing at least one free sulfhydryl group (-SH), wherein the free sulfhydryl group can be obtained by reducing the ligand through a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl) phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, the disulfide bond (-S-S-) between the ligand chains can be reduced to form a free thiol group;
- the compound represented by any formula (I-C) or formula (II-C) of the present application is incubated in an alkaline buffer at a selected temperature for a certain period of time to obtain another formula of any one of the present application.
- Tr, L 2 and L 3 can be respectively as defined in Tr I , L I-2 and L I-3 in the compound represented by any formula (ID) of the present application, or as represented by any formula (II-D) of the present application Tr II , L II-2 and L II -3 in the compound of In the compound represented by the formula (II-C), Ab II and Na -II are defined;
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, diphosphate dibasic Potassium hydrogen-dipotassium phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine - HCl buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, ammonia water-ammonium chloride Buffer, sodium barbital-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium
- Ligand Ab and any compound of formula (I-D) or formula (II-D) of the present application having a group capable of coupling with 2 sulfhydryl groups are reacted in an acidic, neutral or basic buffer to obtain formula ( I-C) or a compound represented by formula (II-C);
- the compound of formula (ID) having a group capable of coupling with 2 sulfhydryl groups may contain an L1 x group selected from the group consisting of: wherein each of R L1a , R L1b and R L1c is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O )H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O)H, -S(O)2H, -C ( O) NH2 , -SO2NH2 , -OC(O)H, -N(H ) SO2H , alkyl, alkenyl, alkynyl, alicyclic, heterocyclyl, aryl and heteroaryl ;
- Ab is a ligand containing at least 2 free sulfhydryl groups (-SH), wherein the free sulfhydryl groups can be obtained by reducing the ligand by a reducing agent;
- the reducing agent includes but is not limited to tris(2-carboxyethyl) phosphine, mercaptoethanol, Dithiothreitol, cysteine, reduced glutathione, etc.; in particular, the disulfide bond (-S-S-) between the ligand chains can be reduced to form a free thiol group;
- Tr, L 1 , L 1x , L 2 , L 3 can be respectively Tr I , L I-1 , L I-1x , L I-2 , L I-3 in the compound represented by any formula (ID) of the present application as defined in any of the compounds represented by the formula (II-D) of the present application, as defined by Tr II , L II-1 , L II-1x , L II-2 and L II-3 ;
- Ab and Na can be respectively As defined by Ab I and N aI in any compound represented by formula (IC) of the present application, or as defined by Ab II and Na -II in any compound represented by formula (II-C) of the present application;
- the buffer is selected from the following buffers at pH 2 to 12, citric acid-sodium citrate buffer, phosphate-sodium phosphate buffer, phosphate-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, diphosphate dibasic Potassium hydrogen-dipotassium phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine - HCl buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, ammonia water-ammonium chloride Buffer, sodium barbital-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium
- NMR nuclear magnetic resonance
- MS mass spectrometry
- UPLC was measured with a Waters AcquityUPLCSQD LC/MS instrument (Poroshell 120 EC-C18, 2.1 mm x 50 mm, 1.9 micron chromatographic column).
- HPLC measurement was performed using an Agilent 1260 high pressure liquid chromatograph (TOSOH G3000 SW SEC column).
- UV was measured using a Thermoanodrop 2000 UV spectrophotometer.
- EnVision microplate reader (PerkinElmer) was used for ELISA.
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm0.2mm, and the specification used for TLC separation and purification products is 0.4mm0. 5mm silicone rubber sheet.
- the known starting materials of this application can be synthesized by using or according to methods known in the art, or can be purchased from companies such as ABCRGmbH & Co.KG, AcrosOrganics, Aldrich Chemical Company, AccelaChemBioInc, Darui Chemicals, etc.
- Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
- Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
- the solution in the reaction refers to an aqueous solution.
- reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, and the temperature range is 20°C to 30°C.
- the eluent system for column chromatography and the developing solvent system for thin layer chromatography used for purifying the compound include: A: dichloromethane and isopropanol system, B: dichloromethane and methanol system, C: petroleum ether and In the ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and an acidic or basic reagent can also be added for adjustment.
- TOF-LC/MS used an Agilent 6230 time-of-flight mass spectrometer and an Agilent 1290-Infinity ultra-performance liquid chromatograph.
- Step 2 (9H-Fluoren-9-yl)methyl((S)-1-((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10- Cyclohexyl-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- Naphthalene[2',1':4,5]indeno[1,2-d][1,3]dioxa-8b-yl)-2-oxoethoxy)methyl)amino)-1- Synthesis of oxypropan-2-yl)carbamate
- Step 2 (9H-Fluoren-9-yl)methyl(2-(((2-(((6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-cyclohexyl-7- Hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphthalene[2,1 : 4,5]Indeno[1,2-d][1,3]dioxa-8b-yl)-2-oxoethoxy)methyl)amino)-2-oxoethyl)amino Synthesis of Formate
- Step 7 Synthesis of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)glycylglycyl-L-phenylalanine
- Step 4 (9H-Fluoren-9-yl)methyl(2-(((2-(((6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-cyclohexyl-7- Hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphthalene[2,1 : 4,5]Indeno[1,2-d][1,3]dioxa-8b-yl)-2-oxoethoxy)methyl)amino)-2-oxoethyl)amino Synthesis of Formate
- Step 1 1-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16-tetraoxo-4-aza Synthesis of dodecane-19-oleic acid
- Step 3 (1-(2,5-Dioxo-2-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16-tetraoxo-4--4 -Synthesis of azadodecane-19-yl)glycylglycyl-L-phenylalanine
- Step 1 Benzyl(S)-47-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-41-oxo-2,5,8,11,14,17,20 Synthesis of ,23,26,29,32,35,38-tridecaoxa-42-azaoctane-48-ester
- Step 3 Benzyl((S)-47-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-41-oxo-2,5,8,11,14,17, Synthesis of 20,23,26,29,32,35,38-Tridecaoxa-42-azaoctane-48-acyl)glycylglycyl-L-phenylalanine
- Step 4 ((S)-47-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-41-oxo-2,5,8,11,14,17,20,23, Synthesis of 26,29,32,35,38-tridecaoxa-42-azaoctane-tetrahydrofuran-48-acyl)glycylglycyl-L-phenylalanine
- Step 5 (9H-Fluoren-9-yl)methyl((47S,56S)-56-benzyl-65-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10 -Cyclohexyl-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH -naphthalene[2',1':4,5]indeno[1,2-d][1,3]dioxo-8b-yl)-41,48,51,54,57,60,65- Heptaoxo-2,5,8,11,14,17,20,23,26,29,32,35,38,63-tetradecane-42,49,52,55,58,61-hexaazide Synthesis of Hetericosicosan-
- Step 1 (9H-Fluoren-9-yl)methyl((S)-10-benzyl-1-(((6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-ring Hexyl-7-hydroxy-6a, 8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphthalene [2',1':4,5]indeno[1,2-d][1,3]dioxa-8b-yl)-1,6,9,12,15-pentoxa-3- Oxa-5,8,11,14-tetraazahexadecan-16-yl)carbamate
- 3,4-Dibromofuran-2,5-dione (25.6 g, 100 mmol) and 3-aminopropionic acid (13.1 g, 100 mmol) were added to 500 ml of toluene, 20 ml of AcOH was added, heated to 120° C. and stirred for 3 hours. After that, the reaction mixture was cooled to room temperature, and the solvent was spin-dried and repeatedly spin-dried with MTBE to take away the AcOH.
- Step 3 (S)-N-(2-((((2-(((6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-cyclohexyl-7-hydroxy-6a, 8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphthalene[2',1':4 ,5]Indeno[1,2-d][1,3]dioxa-8b-yl)-2-oxoethoxy)methyl)amino)-2-oxoethyl)-2-(2 -(2-(3-(3,4-Dibromo-2,5-dioxa)-2,5-dihydro-1H-pyrrol-1-yl)propionamido)acetamido)acetamido )-3-Phenylpropion
- Step 1 Compounds 10A (5 g, 12.68 mmol), 10B (2.57 g, 16 mmol), NaHCO3 (1.43 g, 17 mmol) were dissolved in DME (50 mL), H2O (20 mL) under nitrogen blanket and stirred at room temperature for 17 Hour. The end of the reaction was monitored by LCMS. The reaction solution was concentrated, poured into 100 mL of water, extracted with EA (100 mL), adjusted to pH 2-3 with 5% HCl, separated and washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , spin-dried and concentrated to obtain 5.5 g of white Solid 10C, yield: 98%. MS-ESI: m/z 441.0 [M+H] + .
- Step 4 To compound 10G (3.5 g) in DCM (48 mL) was added DEA (16 mL) and reacted at 0°C for 2 hours. TLC showed the reaction was complete. The reaction solution was concentrated, dissolved in DCM (50 mL*3) and spin-dried, and then reversed to obtain 800 mg of white solid 10H, yield: 30%. MS-ESI: m/z 557.3 [M+H] + .
- Step 6 Under nitrogen protection, a solution of compound 10I (300 mg, 0.306 mmol) in THF (6 mL) was added dropwise 5% LiOH aqueous solution (2 mL) at 0 °C and reacted at 0-5 °C for 2 hours. LCMS showed the reaction was complete. After the reaction solution was extracted twice with PE (30 mL) and H 2 O (30 mL), the aqueous phase was buffered with Na 2 HPO 4 and NaH 2 PO 4
- Step 7 To a solution of compound 10J (65 mg, 0.087 mmol), TEA (88.5 mg, 0.87 mmol) in THF (3 mL) and H 2 O (0.5 mL) under nitrogen protection was added bromoacetyl bromide (70 mg, 0.35 mmol) , and reacted at 0 °C for 10 min. LCMS showed complete reaction of starting material. The reaction solution was directly sent to the preparation and purified to obtain 21 mg of white solid 10, yield: 27.7%. MS-ESI: m/z 863.3 [M+H] + .
- Step 2 Compound 11B (4.3 mmol, 1.58 g) and compound 11C (400 mg, 0.86 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), replaced with nitrogen three times, cooled to -65 degrees, and added with lithium tert-butoxide solution (0.07 eq) and stirred at -65 degrees for 30 minutes. The disappearance of starting material was monitored by TLC.
- Step 3 Ethylenediamine (1 mL) was added dropwise to compound 11D (280 mg, 0.36 mmol) in DCM (5.6 ml) at 0 °C under nitrogen protection, and stirred at 0 °C for 1.5 h.
- LC-MS showed complete reaction of starting material.
- the reaction was added dropwise to 50 ml of tertiary methyl ether, and a white solid was precipitated, which was filtered and washed twice with tertiary methyl ether (50 mL). .
- Step 5 Under the protection of argon, TFA (15 ml) was added to a solution of compound 11H (6 g, 10.7 mmol) in DCM (140 ml), and the reaction was carried out at 25 degrees for 16 h. LCMS showed that the reaction was completed, and the organic phase was directly spin-dried, MTBE (30ml) beating for 16h, and filtering to obtain 5g of white powder 11I with a yield of 92%.
- tris(2-carboxyethyl)phosphine 10mM, 0.092mL, 0.924 ⁇ mol
- K562 cells were seeded at 500,000 cells per well in 2 mL of complete growth medium (RPMI, 10% FBS, 1% L- Glutamine, 1% sodium pyruvate and 1% MEMNEAA (non-essential amino acid solution)) on a 6-well dish ((Costar) Costar: 3516). The next day, 1.5 ⁇ g of pGL4.36 [Luc2P/MMTV/Hygro] (Promega) and 3 uL of PLUS reagent (Invitrogen) were diluted into 244 ⁇ L of Opti-MEM (Gibco: 31985-070) and incubated at room temperature Incubate for 15 minutes.
- complete growth medium RPMI, 10% FBS, 1% L- Glutamine, 1% sodium pyruvate and 1% MEMNEAA (non-essential amino acid solution)
- the pGL4.36[luc2P/MMTV/Hygro] vector contains a murine mammary tumor virus long terminal repeat that drives a luciferase reporter gene in response to activation of several nuclear receptors, such as the glucocorticoid receptor and androgen receptor Transcription of luc2P.
- the diluted DNA solution was pre-incubated with 1:1 Lipofectamine LTX solution (13.2 ⁇ L + 256.8 ⁇ L Opti-MEM) and incubated at room temperature for 25 min to form DNA-Lipofectamine LTX complex. After incubation, 500 ⁇ L of DNA-lipofectin complex was added directly to the wells containing cells.
- K562 cells were transfected for 24 h at 37 °C, 5% CO2 . After incubation, cells were washed with 3 mL of PBS and selected for two weeks with complete growth medium containing 125 ⁇ g/mL of hygromycin B. "K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]" cells were generated.
- mFL_TNF ⁇ DNA encoding unlabeled mouse TNF and 3 ⁇ L of PLUS reagent were diluted into 244 ⁇ L of Opti-MEM (Gibco: 31985-070) and incubated at room temperature 15 minutes. After incubation, the diluted DNA solution was pre-incubated with 1:1 Lipofectamine LTX solution) (13.2 ⁇ L + 256.8 ⁇ L Opti-MEM) and incubated at room temperature for 25 min to form DNA-Lipofectamine LTX complexes thing. After incubation, 500 ⁇ L of DNA-lipofectin complex was added directly to the wells containing cells.
- K562pGL4.36 ⁇ [Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV] cells were transfected for 24 hours at 37°C, 5% CO2 . After incubation, cells were washed with 3 mL of PBS and selected for two weeks with complete growth medium containing 125 ⁇ g/mL hygromycin B (Invitrogen: 10687-010) and 250 ⁇ g/mL G418 (Gibco: 10131-027). "K562 mouse FL-TNF ⁇ GRE(pGL4.36[luc2P/MMTV/Hygro])" cells were generated.
- the parental cells K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV] were transfected with the plasmid hTNF ⁇ 1-12C-MycpcDNA3.1(-) plasmid construct .
- the plasmid was pcDNA3.1 (Thermo Fisher, Cat. No. V79020), which encodes tace-resistant transmembrane TNF. (See Perez C et al., Cell 63(2):251-8 (1990), which discusses tace-resistant transmembrane TNF.).
- "K562 human TNF[delta]l-12GRE(pGL4.36[luc2P/MMTV/Hygro])" cells were generated. These cell lines were then used in the TNF-alpha reporter assay described in the Examples that follow.
- K562 parental GRE cells (“K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]” cells), and GRE-mouse TNF- ⁇ cells (“K562 mouse FL-TNF ⁇ GRE(pGL4.36 [luc2P/MMTV/Hygro])” cells) or GRE-human TNF- ⁇ cells (“K562 human TNF ⁇ 1-12GRE(pGL4.36[luc2P/MMTV/Hygro])” cells) were seeded at 50,000 cells per well 96-well plate.
- the ligand-drug conjugate (ADC) of the present application was serially diluted 3X with medium and added to the above-mentioned 96-well plate, and incubated at 37° C., 5% CO 2 for 48 hours. Luminescence was analyzed after treatment with a luciferase assay system. Data were analyzed using a four-parameter curve fit to generate EC50 values. The % maximum activation was normalized to 100 nM dexamethasone.
- Test Example 2.2 Lipopolysaccharide (LPS)-induced cytokine release and downstream signal detection
- PBMC Primary human peripheral blood mononuclear cells
- FBS fetal bovine serum
- DMSO fetal bovine serum
- DMSO fetal bovine serum
- PBMCs are thawed, resuspended in cell culture medium (eg, RPMI cell culture medium) with 2% FBS and 1% penicillin-streptomycin, and seeded in 96-well plates.
- Cells were then incubated with different concentrations of ADC for 4 h at 37 °C and 5% CO . Treated with a certain concentration of stimuli such as lipopolysaccharides (LPS) for a certain period of time.
- LPS lipopolysaccharides
- the plate was then spun at 1000 rpm for 5 minutes, and 100 ⁇ L of the supernatant medium was directly transferred to another 96-well plate and analyzed for cytokine concentrations such as IL-6 and IL-1 ⁇ , and phosphorylated STAT1 levels.
- ADC ligand-drug conjugate
- ADCs were evaluated in an acute contact hypersensitivity model by applying a sensitizer (fluorescein isothiocyanate, FITC), using a delayed type hypersensitivity (DTH) response (T cell driven ) causes acute skin inflammation.
- the efficacy of the Ligand Drug Conjugates (ADCs) of the present application was measured by their ability to reduce ear swelling. Including detection of biomarkers, such as steroids, corticosterone, and procollagen type 1 N-terminal propeptide (P1NP), to assess the effect of the ligand-drug conjugates (ADC) of the present application on the hypothalamic-pituitary-adrenal (HPA) axis, respectively and bone turnover (bone resorption and bone formation).
- biomarkers such as steroids, corticosterone, and procollagen type 1 N-terminal propeptide (P1NP)
- mice On day 0, mice were placed under general anesthesia and their abdomens were shaved. Mice were sensitized by intraperitoneal injection of 400 [mu]L of a FITC solution (1:1 acetone: 1.5% solution in DBP (dibutyl phthalate)) using a micropipette.
- FITC FITC solution
- mice Six days later, 1 hour before ear injection with FITC, mice were dosed (control group solvent or treatment group Ligand Drug Conjugate of the present application).
- mice For ear injection, mice were placed under general anesthesia and re-sensitized with 20 ⁇ l of FITC in the right ear. Twenty-four hours after resensitization, the mice were under general anesthesia, and the ear thickness was measured by a vernier caliper. Calculate the difference between sensitized and non-sensitized ears.
- the results show that the ligand-drug conjugate (ADC) of the present application has the ability to affect the swelling of ear skin, and the ligand-drug conjugate (ADC) of the present application can be used to prevent and/or treat inflammatory diseases and/or symptoms.
- mice 72 hours after ear sensitization, mice were intraperitoneally injected with ACTH (adrenocorticotropic hormone) at 1 mpk (mg/kg) and terminally bled 30 minutes after ACTH administration. Plasma was collected and analyzed for procollagen type 1 N-terminal propeptide (P1NP), corticosterone, free steroid, and macromolecule levels.
- ACTH asdrenocorticotropic hormone
- Calibration curves for steroids were prepared in mouse plasma at various (eg, 8) different concentration levels with final concentrations ranging from 0.03 nM to 0.1 ⁇ M.
- a corticosterone calibration curve was prepared ranging from 0.3 nM to 1 ⁇ M final corticosterone concentration in a 70 mg/mL solution of bovine serum albumin in PBS buffer.
- a solution of 160 ⁇ L of MeCN (acetonitrile) containing 0.1% formic acid was added to 40 ⁇ L of the test plasma sample or calibration standard. The supernatant was diluted with distilled water and 30 ⁇ L of the final sample solution was injected for LC/MS analysis.
- P1NP plasma procollagen type 1 N-terminal propeptide
- LCMS platform As a special type I collagen precipitation indicator, the level of P1NP reflects the status of osteoblast activity and bone formation. Plasma samples were partially precipitated and completely reduced by the addition of a MeCN/0.1 M ammonium bicarbonate/DTT (dithiothreitol) mixture. The supernatant was collected and alkylated by addition of iodoacetic acid. Alkylated proteins were digested by trypsin and the resulting trypsinized peptides were analyzed by LC/MS.
- MeCN/0.1 M ammonium bicarbonate/DTT dithiothreitol
- the results show that the ligand-drug conjugate (ADC) of the present application has little effect on free steroid, endogenous corticosterone, and plasma P1NP levels, and the ligand-drug conjugate (ADC) of the present application has biological safety.
- ADCs ligand-drug conjugates
- mice Male DBA/1J mice were obtained from Jackson Labs. Mice were used when they were 6 to 8 weeks old. All animals were given free access to food and water at constant temperature and humidity on a 12-hour light/dark cycle. Body weight and condition were monitored and animals were euthanized if >20% weight loss was exhibited.
- mice The base of the tail was treated with 100 ⁇ L of an emulsion containing 100 ⁇ g of bovine collagen type II dissolved in 0.1 N acetic acid and 200 ⁇ g of heat-killed Mycobacterium tuberculosis H37Ra (complete Freund’s adjuvant, Difco, Laurence, KS) intradermally at the base of the tail ( i.d. intradermal injection) immunize male DBA/J mice. Twenty-one days after immunization with collagen, mice were injected intraperitoneally with 1 mg of Zymosan A (Sigma, St. Louis, MO) in PBS. Following peritoneal injection, mice were monitored for arthritis 3 to 5 times per week. Hind paws were assessed for paw swelling using Dyer spring calipers (Dyer 310-115). Mice were enrolled between days 24 and 28 at the first clinical sign of disease and assigned to groups of equivalent arthritis severity. Early therapeutic treatment was started at enrollment.
- H37Ra complete Freund’s adjuvant, Difco
- the ligand-drug conjugate (ADC) of the present application has the ability to reduce the swelling of the hind paw in mice, and can show a prolonged duration of action of about 28 days.
- Antibody drug conjugates (ADCs) have the ability to reduce arthritis severity and biosafety (eg, blood safety).
- Test Example 2.5 Lipopolysaccharide (LPS)-induced cytokine release and downstream signal detection
- PBMC Primary human peripheral blood mononuclear cells
- FBS fetal bovine serum
- DMSO fetal bovine serum
- PBMCs are thawed, resuspended in cell culture medium (eg, RPMI cell culture medium) with 2% FBS and 1% penicillin-streptomycin, and seeded in 96-well plates at 2 x 106 cells per well. Cells were then incubated with various concentrations of ADCs described herein for 4 hours at 37°C and 5% CO2 .
- PBMC Primary human peripheral blood mononuclear cells
- FBS fetal bovine serum
- DMSO fetal bovine serum
- PBMCs are thawed, resuspended in cell culture medium (eg, RPMI cell culture medium) with 2% FBS and 1% penicillin-streptomycin, and seeded in 96-well plates at 2 x 106 cells per well. Cells were then incubated with various concentrations of ADCs described herein for 4 hours at 37°C and 5% CO2 .
- PBMC Primary human peripheral blood mononuclear cells
- FBS fetal bovine serum
- DMSO fetal bovine serum
- PBMCs are thawed, resuspended in cell culture medium (eg, RPMI cell culture medium) with 2% FBS and 1% penicillin-streptomycin, and seeded in 96-well plates at 2 x 106 cells per well. Cells were then incubated with various concentrations of ADCs described herein for 4 hours at 37°C and 5% CO2 .
- ADCs were evaluated in an acute contact hypersensitivity model by applying a sensitizer (fluorescein isothiocyanate, FITC), using a delayed type hypersensitivity (DTH) response (T cell driven ) causes acute skin inflammation.
- FITC fluorescein isothiocyanate
- DTH delayed type hypersensitivity
- the efficacy of the Ligand Drug Conjugate (ADC) of the present application was measured by its ability to reduce ear swelling
- mice were placed under general anesthesia and their abdomens were shaved. Mice were sensitized by intraperitoneal injection of 400 [mu]L of a FITC solution (1:1 acetone: 1.5% solution in DBP (dibutyl phthalate)) using a micropipette.
- mice were dosed (control group solvent or treatment group Ligand Drug Conjugate of the present application).
- FITC FITC solution
- mice were placed under general anesthesia and re-sensitized with 20 ⁇ l of FITC in the right ear. Twenty-four hours after resensitization, the mice were under general anesthesia, and the ear thickness was measured by a vernier caliper. Calculate the difference between sensitized and non-sensitized ears. The results are shown in Figure 4. Compared with the monoclonal antibody, the ligand-drug conjugate of the present application can significantly reduce the degree of ear swelling in mice.
- DBA/1J mice were obtained from Jackson Labs. Mice were used when they were 6 to 8 weeks old. All animals were placed on a 12-hour light/dark cycle with free access to food and water at constant temperature and humidity. Body weight and condition were monitored and animals were euthanized if >20% weight loss was exhibited.
- mice The base of the tail was treated with 100 ⁇ L of an emulsion containing 100 ⁇ g of bovine collagen type II dissolved in 0.1 N acetic acid and 200 ⁇ g of heat-killed Mycobacterium tuberculosis H37Ra (complete Freund’s adjuvant, Difco, Laurence, KS) intradermally at the base of the tail ( i.d. intradermal injection) immunize male DBA/J mice. Twenty-one days after immunization with collagen, mice were injected intraperitoneally with 1 mg of Zymosan A (Sigma, St. Louis, MO) in PBS. Following peritoneal injection, mice were monitored for arthritis 3 to 5 times per week. Hind paws were assessed for paw swelling using Dyer spring calipers (Dyer 310-115). Mice were enrolled between days 24 and 28 at the first clinical sign of disease and assigned to groups of equivalent arthritis severity.
- H37Ra complete Freund’s adjuvant, Difco, Laurence, KS
- Animals were dosed once intraperitoneally (i.p.) with either the control antibody (high dose) or the Ligand Drug Conjugate (ADC) of the present application (7 mg/kg and 20 mg/kg) in 0.9% saline. After administration, the paw thickness was measured every 2 to 3 days, and a score was given according to the paw thickness (each paw was rated as 0 to 4 points according to the degree of swelling, and the total score was 16 points). The results are shown in FIG. 5 , compared with the vehicle blank reagent, the ligand-drug conjugate (ADC) of the present application has the ability to reduce the swelling of the mouse paw.
- ADC Ligand Drug Conjugate
- the inhibitory effect of the ligand-drug conjugate (ADC) of the present application on the production of IFN ⁇ by plasmacytoid dendritic cells was detected.
- Plasmacytoid dendritic cells were treated with different concentrations of ligand-drug conjugates in vitro, and the IFN ⁇ produced by plasmacytoid dendritic cells was quantitatively detected after a certain period of time.
- the in vitro activity of the Ligand Drug Conjugates was evaluated according to IC50.
- Human peripheral blood mononuclear cells are resuspended in RPMI complete medium, seeded into a 96-well plate at 0.5-1 ⁇ 10 6 /well, and the gradient-diluted ligand-drug conjugate of the present application is added thereto. Then, a fixed concentration of stimulators CpG-A or R848 or systemic lupus erythematosus SLE immune complex (Sm/RNP antigen and anti-RNP antibody were mixed in a certain ratio) were added to the system, and cultured at 37°C overnight. The supernatant was collected, and the level of IFN ⁇ in the supernatant was detected by a kit. The dose-response data were fitted to a sigmoid curve using nonlinear regression and IC50 values were calculated.
- Plasmacytoid dendritic cells were isolated from human peripheral blood mononuclear cells using the plasmacytoid dendritic cell isolation kit (Miltenyi), suspended in RPMI complete medium, and inoculated into 96 wells at 0.5-2 ⁇ 10 5 /well, A serial dilution of the ligand-drug conjugate of the present application is added thereto. Then, a fixed concentration of stimulator CpG-A or R848 or SLE immune complex (Sm/RNP antigen and anti-RNP antibody were mixed in a certain ratio) were added to the system, and incubated at 37°C overnight. The supernatant was collected, and the level of IFN ⁇ in the supernatant was detected by a kit. The dose-response data were fitted to a sigmoid curve using nonlinear regression and IC50 values were calculated.
- the ligand-drug conjugate of the present application may have the ability to inhibit inflammation, and may be used for the prevention and/or treatment of diseases and/or conditions such as inflammation.
- Test example 3.2 Type I interferon-induced response element signal detection
- the pHTS-ISRE luciferin reporter gene plasmid was constructed into HEK293 cells to construct a reporter system for type I interferon response signal.
- Cells were cultured in DMEM medium containing a certain concentration of FBS and Geneticin, to which was added a series of diluted ligand-drug conjugates and a certain concentration of plasmacytoid dendritic cells-induced type I interferon IFN or recombinant type I interferon. Incubation. Cells were lysed, fluorescein intensities were determined, and the dose-response data were fitted to a sigmoid curve using nonlinear regression, and IC50 values were calculated.
- the ligand-drug conjugate of the present application may have the ability to inhibit inflammation, and may be used for the prevention and/or treatment of diseases and/or conditions such as inflammation.
- Test example 3.3 Cytokine release induced by CpG-A and detection of downstream signaling molecules
- PBMC Primary human peripheral blood mononuclear cells
- FBS fetal bovine serum
- DMSO fetal bovine serum
- DMSO fetal bovine serum
- PBMCs are thawed, resuspended in cell culture medium (eg, RPMI cell culture medium) with 2% FBS and 1% penicillin-streptomycin, and seeded in 96-well plates.
- Cells were then incubated with varying concentrations of ligand-drug conjugates at 37°C and 5% CO2 . Treatment with a certain concentration of CpG-A or other stimuli for a certain period of time.
- the plate was then spun at 1000 rpm for 5 minutes, and 100 ⁇ L of the supernatant medium was directly transferred to another 96-well plate and analyzed for cytokine levels such as IL-6 and IL-1 ⁇ .
- a certain concentration of ligand-drug conjugate was added to human peripheral blood mononuclear cells for culture. Then, a certain concentration of plasmacytoid dendritic cells induced type I interferon IFN or recombinant type I interferon was added for incubation. Cells were lysed for electrophoresis and western blot detection, and STAT1 phosphorylation levels were determined using anti-human STAT1pTY701 antibody.
- ADC ligand-drug conjugate
- the ligand-drug conjugate (ADC) of the present application was applied to a human plasmacytoid dendritic cell xenograft mouse model, and the in vivo efficacy of the ligand-drug conjugate was evaluated by means of immunohistochemistry and gene transcription analysis.
- mice Severely immunodeficient mice (CB17/Icr-Prkdcscid/IcrIcoCrl, Charles River), 4 to 8 weeks old, were used to shave their backs. A 5% imiquimod cream was applied to the back of the mice and a second application was performed 12 hours later. Subsequently, mice were intraperitoneally injected with a certain concentration of the ligand-drug conjugate of the present application or the control ligand-drug conjugate. Twelve hours later, mice were injected with 1-10x105 human plasmacytoid dendritic cells into the tail vein. After an additional 12-hour incubation, the mice were euthanized, and back skin samples were collected for testing.
- mice Severely immunodeficient mice (CB17/Icr-Prkdcscid/IcrIcoCrl, Charles River), 4 to 8 weeks old, were used to shave their backs.
- a concentration of bleomycin was injected subcutaneously at a single site on the back of the mice, once every two days for three weeks.
- 1-10x105 human plasmacytoid dendritic cells were injected into the tail vein of mice on days 0, 7, and 14 of the first bleomycin injection. 24 hours before the first injection of bleomycin, mice were intraperitoneally injected with a certain concentration of the ligand-drug conjugate of the present application or the control ligand-drug conjugate, once every 5 days.
- the kit extracts mouse skin cell RNA and reverse-transcribes it into cDNA. Using Real-time PCR, the mouse sample treated with the control ligand-drug conjugate is used as a control to determine the effect of the ligand-drug conjugate on type I IFN signaling pathway responds to the effects of gene transcription.
- mice skin samples were formalin-fixed and embedded in paraffin, and the paraffin was sectioned at 5 ⁇ M for hematoxylin-eosin staining. The degree of fibrosis in the skin samples was identified by Masson staining. Immunohistochemical analysis was performed with pSTAT1Tyr701 antibody.
- the ligand-drug conjugate of the present application can have the ability to inhibit inflammation in vivo, and can be used for the prevention and/or treatment of diseases and/or conditions such as inflammation.
- Pharmacokinetics After a single intravenous infusion of different doses of the ligand-drug conjugate (ADC) of the present application, blood samples were collected at multiple consecutive time points, and the concentration of the drug in the blood was detected by a specific detection method.
- ADC ligand-drug conjugate
- Toxicity study After a single intravenous infusion of different doses of the ligand-drug conjugate (ADC) of the present application, monkeys were investigated through clinical observation, body weight and food intake, hematology, blood biochemistry, urine, gross anatomy, etc. Tolerability in animals, and manifestations of drug-related toxicity.
- ADC ligand-drug conjugate
- Test Example 3.5 Inhibition test of cytokine production by human peripheral blood mononuclear cells
- PBMC Primary human peripheral blood mononuclear cells
- FBS fetal bovine serum
- DMSO fetal bovine serum
- PBMCs are thawed, resuspended in cell culture medium (eg, RPMI cell culture medium) with 2% FBS and 1% penicillin-streptomycin, and seeded in 96-well plates at 2 x 106 cells per well. Cells were then incubated with various concentrations of ADCs described herein for 4 hours at 37°C and 5% CO2 .
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Abstract
涉及一种甾体偶联物,具体涉及化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐。还涉及本申请化合物的制备方法及其应用。
Description
本申请涉及生物医药领域,具体的涉及一种甾体偶联物。
目前,用于甾体偶联物的抗体偶联药物以及甾体类化合物,通过作用于糖皮质激素受体信号等分子,可以用于炎症等疾病或症状的治疗。目前的甾体偶联物的抗体偶联药物以及甾体类化合物在疗效和安全性方面仍有缺陷,因此目前急需进一步开发多种甾体形成的抗体偶联药物以及甾体类化合物,以作为可以发挥更好的疗效和/或可以具有更好的安全性的药物。
发明内容
本申请提供了一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其可以具有选自以下组的一种或多种效果:(1)具有影响免疫细胞活性的能力;(2)具有靶向作用;(3)具有血浆稳定性;(4)具有生物安全性;(5)具有影响免疫细胞的细胞因子释放的能力;(6)具有影响IFN信号途径应答基因转录的能力;(7)具有影响皮肤纤维化程度的能力;(8)具有影响树突状细胞数量和/或比例的能力;(9)具有影响皮肤胶原含量的能力;(10)具有影响GRE表达水平的能力;(11)具有影响单核细胞细胞因子释放的能力;(12)具有影响接触性超敏反应的能力;(13)具有影响皮肤肿胀的能力;和(14)具有影响关节炎症状的能力。
一方面,本申请提供了一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物包含式(I-A)所示的结构:
其中,Tr
I包含-(SP
I-1)
nI-1-,
每一个SP
I-1各自独立地为-N(R
I-1c)-C(R
I-1a)(R
I-1b)-,
每一个R
I-1a、R
I-1b和R
I-1c各自独立地不存在,或每一个R
I-1a、R
I-1b和R
I-1c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=S、-OR
I-2、-SR
I-2、-N(R
I-a)(R
I-2b)、-C(=O)R
I-
2、-C(=O)OR
I-2、-C(=O)C(=O)R
I-2、-C(=O)CH
2C(=O)R
I-2、-S(=O)R
I-2、-S(=O)
2R
I-2、-C(=O)N(R
I-
2a)(R
I-2b)、-SO
2N(R
I-2a)(R
I-2b)、-OC(=O)R
I-2、和-N(R
I-2a)SO
2R
I-2b;或每一个R
I-1a、R
I-1b和R
I-1c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R
I-
1a、R
I-1b和R
I-1c各自独立地不被取代,或每一个R
I-1a、R
I-1b和R
I-1c各自独立地被至少1个R
I-
2取代;或每一个R
I-1a和R
I-1b各自独立地与它们之间的原子一起形成选自以下组的环A
I:脂环基、杂环基、芳基和杂芳基,其中每一个环A
I各自独立地不被取代,或每一个环A
I各自独立地被至少1个R
I-2取代;
其中,每一个R
I-2,R
I-2a和R
I-2b各自独立地不存在,或每一个R
I-2,R
I-2a和R
I-2b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH
2C(=O)H、-S(=O)H、-S(=O)
2H、-C(=O)NH
2、-SO
2NH
2、-OC(=O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,R
I-G1和R
I-G2各自独立地选自以下组:氢、卤素和烷基,R
I-G3选自以下组:O、S和N;
其中,nI-1至少为1。
在一种实施方式中,其中,R
I-G1为氢,R
I-G2为氢。
在一种实施方式中,其中,R
I-G3为O。
在一种实施方式中,其中,nI-1为1。
在一种实施方式中,其中,每一个R
I-1a和R
I-1b各自独立地选自以下组:氢、烷基和被至 少1个R
I-2取代的烷基。
在一种实施方式中,其中,每一个R
I-1a和R
I-1b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-1a和R
I-1b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个R
I-1c各自独立地选自以下组:氢、烷基和被至少1个R
I-2取代的烷基。
在一种实施方式中,其中,每一个R
I-1c各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-1c各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个R
I-2,R
I-2a和R
I-2b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-2,R
I-2a和R
I-2b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个SP
I-1各自独立地选自以下组:-NH-CH
2-、-NH-CH(CH
3)-、-NH-C(CH
3)
2-、-N(CH
3)-CH
2-、-N(CH
3)-CH(CH
3)-和-N(CH
3)-C(CH
3)
2-。
在一种实施方式中,其中,每一个SP
I-1各自独立地选自以下组:-NH-CH
2-、-NH-CH(CH
3)-、-N(CH
3)-CH
2-、和-N(CH
3)-C(CH
3)-。
在一种实施方式中,其中,Tr
I还包含-SP
I-2-,
SP
I-2为-(C(R
I-3a)(R
I-3b))
nI-2-,
其中,SP
I-2的每一个亚甲基单元不被替代;或SP
I-2的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy
I-1-、-N(R
I-3c)C(=O)-、-C(=O)N(R
I-3c)-、-C(=O)-、-OC(=O)-、-C(=O)O-、-NR
I-3c-、-O-、-S-、-SO-、-SO
2-、-P(R
I-3c)-、-P(=O)(R
I-3c)-、-N(R
I-3c)SO
2-、-SO
2N(R
I-3c)-、-C(=S)-、-C(=NR
I-3c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N
2)-,其中,每一个Cy
I-1各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个Cy
I-1各自独立地不被取代,或每一个Cy
I-1各自独立地被至少1个R
I-3c取代;
其中,每一个R
I-3a、R
I-3b和R
I-3c各自独立地不存在,或每一个R
I-3a、R
I-3b和R
I-3c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OR
I-4、-SR
I-4、-N(R
I-4a)(R
I-
4b)、-C(=O)R
I-4、-C(=O)OR
I-4、-C(=O)C(=O)R
I-4、-C(=O)CH
2C(=O)R
I-4、-S(=O)R
I-4、-S(=O)
2R
I-
4、-C(=O)N(R
I-4a)(R
I-4b)、-SO
2N(R
I-4a)(R
I-4b)、-OC(=O)R
I-4、和-N(R
I-4a)SO
2R
I-4b;或每一个R
I-3a、R
I-3b和R
I-3c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R
I-3a、R
I-3b和R
I-3c各自独立地不被取代,或每一个R
I-3a、R
I-3b和R
I-3c各自独立地被至少1个R
I-4取代;或每一个R
I-3a和R
I-3b各自独立地与它们之间的原子一起形成选自以下 组的环B
I:脂环基、杂环基、芳基和杂芳基,其中每一个环B
I各自独立地不被取代,或每一个环B
I各自独立地被至少1个R
I-4取代;
其中,每一个R
I-4,R
I-4a和R
I-4b各自独立地不存在,或每一个R
I-4,R
I-4a和R
I-4b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH
2C(=O)H、-S(=O)H、-S(=O)
2H、-C(=O)NH
2、-SO
2NH
2、-OC(=O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,nI-2至少为0。
在一种实施方式中,其中,nI-2选自以下组:0、1、2和3。
在一种实施方式中,其中,每一个R
I-3a,R
I-3b和R
I-3c各自独立地选自以下组:氢、=O、-OR
I-4、-C(=O)R
I-4、烷基和被至少1个R
I-4取代的烷基。
在一种实施方式中,其中,每一个R
I-3a,R
I-3b和R
I-3c各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-3a,R
I-3b和R
I-3c各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个R
I-4,R
I-4a和R
I-4b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-4,R
I-4a和R
I-4b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,SP
I-2的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R
I-3c)C(=O)-、-C(=O)N(R
I-3c)-、-C(=O)-、-OC(=O)-、-C(=O)O-、-NR
I-3c-和-O-。
在一种实施方式中,其中,SP
I-2的至少1个、至少2个或至少3个亚甲基单元各自独立地被选自以下组的基团替代:-C(=O)-、和-NR
I-3c-。
在一种实施方式中,其中,SP
I-2选自以下组:-(C(R
I-3a)(R
I-3b))
2-、-(C(R
I-3a)(R
I-3b))
3-、-N(R
I-
3c)-C(R
I-3a)(R
I-3b)-C(=O)-、-N(R
I-3c)-(C(R
I-3a)(R
I-3b))
2-和-N(R
I-3c)-(C(R
I-3a)(R
I-3b))
3-。
在一种实施方式中,其中,SP
I-2选自以下组:-(CH
2)
2-、-(CH
2)
3-、-NH-CH
2-C(=O)-、-N(CH
3)-CH
2-C(=O)-、-NH-(CH
2)
2-、-NH-(CH
2)
3-、-N(CH
3)-(CH
2)
2-和-N(CH
3)-(CH
2)
3-。
在一种实施方式中,其中,SP
I-2为氨基酸的残基。
在一种实施方式中,其中,SP
I-2为选自以下组氨基酸的残基:苯丙氨酸、异亮氨酸、亮氨酸、色氨酸、缬氨酸、甲硫氨酸、酪氨酸、丙氨酸、苏氨酸、组氨酸、丝氨酸、谷氨酰胺、精氨酸、赖氨酸、天冬酰胺、谷氨酸、脯氨酸、瓜氨酸、半胱氨酸、天冬氨酸、甘氨酸、缬氨酸、丙氨酸和苯丙氨酸。
在一种实施方式中,其中,SP
I-2为选自以下组氨基酸的残基:谷氨酸、赖氨酸、瓜氨酸、甘氨酸和丙氨酸。
R
I-p选自以下组:H,-CH
3、-CH-(CH
3)
2、-CH
2-CH(CH
3)
2、-CH(CH
3)-CH
2-CH
3、-CH
2-C
6H
5、-C
8NH
6、-CH
2-C
6H
4-OH、-CH
2-COOH、-CH
2-CONH
2、-(CH
2)
2-COOH、-(CH
2)
4-NH
2、-(CH
2)
2-CONH
2、-(CH
2)
2-S-CH
3、-CH
2-OH、-CH(CH
3)-OH、-CH
2-SH、-C
3H
6、-CH
2-C
3H
3N、-(CH
2)
3-NHC(NH)NH
2和-(CH
2)
3-NHCONH
2。
R
I-p选自以下组:H,-CH
3、-(CH
2)
2-COOH、-(CH
2)
4-NH
2和-(CH
2)
3-NHCONH
2。
在一种实施方式中,其中,Tr
I还包含-(SP
I-3)
nI-3-,
每一个SP
I-3各自独立地选自以下组:-O-、-S-、-C(=O)-、-N(R
I-5)-、-O-C(=O)-、-C(=O)-O-、-N(R
I-5)-C(=O)-、-N(R
I-5)-C(R
I-5a)(R
I-5b)-、和-N(R
I-5)-C(R
I-5a)(R
I-5b)-S-,
其中,每一个R
I-5,R
I-5a和R
I-5b各自独立地不存在,或每一个R
I-5,R
I-5a和R
I-5b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH
2C(=O)H、-S(=O)H、-S(=O)
2H、-C(=O)NH
2、-SO
2NH
2、-OC(=O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,nI-3至少为0。
在一种实施方式中,其中,nI-3为1。
在一种实施方式中,其中,每一个R
I-5,R
I-5a和R
I-5b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-5,R
I-5a和R
I-5b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,SP
I-3选自以下组:-O-、-S-、-C(=O)-、-NH-、-N(CH
3)-、-O-C(=O)-、-NH-C(=O)-、-NH-CH
2-、-NH-CH(CH
3)-、-NH-C(CH
3)
2-、-N(CH
3)-CH
2-、-N(CH
3)-CH(CH
3)-、-N(CH
3)-C(CH
3)
2-、-NH-CH
2-S-、-N(CH
3)-CH
2-S-、-NH-CH(CH
3)-S-和-N(CH
3)-CH(CH
3)-S-。
在一种实施方式中,其中,SP
I-3选自以下组:-O-、-S-、-C(=O)-、-NH-、-O-C(=O)-、-C(=O)- O-、-NH-C(=O)-、-NH-CH
2-、和-NH-CH
2-S-。
在一种实施方式中,其中,SP
I-3为-O-C(=O)-。
在一种实施方式中,其中,Tr
I还包含-SP
I-4-,
其中,每一个R
I-6,R
I-7和R
I-8各自独立地不存在,或每一个R
I-6,R
I-7和R
I-8各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH
2C(=O)H、-S(=O)H、-S(=O)
2H、-C(=O)NH
2、-SO
2NH
2、-OC(=O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,nI-4和nI-5各自独立地至少为0。
在一种实施方式中,其中,每一个R
I-6,R
I-7和R
I-8各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-6,R
I-7和R
I-8各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,Tr
I包含-SP
I-2-(SP
I-1)
nI-1-。
在一种实施方式中,其中,Tr
I包含-(SP
I-3)
nI-3-SP
I-2-(SP
I-1)
nI-1-。
在一种实施方式中,其中,Tr
I包含-SP
I-4-(SP
I-3)
nI-3-SP
I-2-(SP
I-1)
nI-1-。
在一种实施方式中,其中,Tr
I选自以下组:
在一种实施方式中,其中,Tr
I选自以下组:
其中,每一个R
I-1a,R
I-1b,R
I-1c和R
I-3c各自独立地选自以下组:氢和C
1-C
6烷基,
R
I-p选自以下组:H,-CH
3、-CH-(CH
3)
2、-CH
2-CH(CH
3)
2、-CH(CH
3)-CH
2-CH
3、-CH
2-C
6H
5、-C
8NH
6、-CH
2-C
6H
4-OH、-CH
2-COOH、-CH
2-CONH
2、-(CH
2)
2-COOH、-(CH
2)
4-NH
2、-(CH
2)
2-CONH
2、-(CH
2)
2-S-CH
3、-CH
2-OH、-CH(CH
3)-OH、-CH
2-SH、-C
3H
6、-CH
2-C
3H
3N、-(CH
2)
3-NHC(NH)NH
2和-(CH
2)
3-NHCONH
2。
在一种实施方式中,其中,Tr
I选自以下组:
其中,R
I-p选自以下组:H,-CH
3、-CH-(CH
3)
2、-CH
2-CH(CH
3)
2、-CH(CH
3)-CH
2-CH
3、-CH
2-C
6H
5、-C
8NH
6、-CH
2-C
6H
4-OH、-CH
2-COOH、-CH
2-CONH
2、-(CH
2)
2-COOH、-(CH
2)
4-NH
2、-(CH
2)
2-CONH
2、-(CH
2)
2-S-CH
3、-CH
2-OH、-CH(CH
3)-OH、-CH
2-SH、-C
3H
6、-CH
2-C
3H
3N、-(CH
2)
3-NHC(NH)NH
2和-(CH
2)
3-NHCONH
2。
在一种实施方式中,其中,Tr
I选自以下组:
其中,R
I-p选自以下组:H,-CH
3、-CH-(CH
3)
2、-CH
2-CH(CH
3)
2、-CH(CH
3)-CH
2-CH
3、-CH
2-C
6H
5、-C
8NH
6、-CH
2-C
6H
4-OH、-CH
2-COOH、-CH
2-CONH
2、-(CH
2)
2-COOH、-(CH
2)
4-NH
2、-(CH
2)
2-CONH
2、-(CH
2)
2-S-CH
3、-CH
2-OH、-CH(CH
3)-OH、-CH
2-SH、-C
3H
6、-CH
2-C
3H
3N、-(CH
2)
3-NHC(NH)NH
2和-(CH
2)
3-NHCONH
2。
一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其 混合物形式,或其可药用的盐,
其中,所述化合物包含选自以下组的结构:
其中,R
I-p选自以下组:H,-CH
3、-CH-(CH
3)
2、-CH
2-CH(CH
3)
2、-CH(CH
3)-CH
2-CH
3、-CH
2-C
6H
5、-C
8NH
6、-CH
2-C
6H
4-OH、-CH
2-COOH、-CH
2-CONH
2、-(CH
2)
2-COOH、-(CH
2)
4-NH
2、-(CH
2)
2-CONH
2、-(CH
2)
2-S-CH
3、-CH
2-OH、-CH(CH
3)-OH、-CH
2-SH、-C
3H
6、-CH
2-C
3H
3N、-(CH
2)
3-NHC(NH)NH
2和-(CH
2)
3-NHCONH
2。
一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物包含式(I-B)所示的结构:
其中,Tr
I为本申请任一项所述的Tr
I,L
I包含L
I-1,L
I-1为二价残基或三价残基,R
I-G1和R
I-G2各自独立地选自以下组:氢、卤素和烷基,R
I-G3选自以下组:O、S和N。
在一种实施方式中,其中,R
I-G1为氢,R
I-G2为氢。
在一种实施方式中,其中,R
I-G3为O。
在一种实施方式中,其中,L
I-1选自以下组:氨基参与偶联形成的二价残基或三价残基、巯基参与偶联形成的二价残基或三价残基、和点击化学偶联形成的二价残基或三价残基。
在一种实施方式中,其中L
I-1选自以下组:
在一种实施方式中,其中L
I-1选自以下组:
R
I-9选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
在一种实施方式中,其中,R
I-9选自以下组:氢和烷基。
在一种实施方式中,其中,R
I-9选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中L
I-1选自以下组:
在一种实施方式中,其中L
I-1选自以下组:
在一种实施方式中,其中,L
I还包含L
I-2,L
I-2不存在,或L
I-2包含-X
I-,
X
I为-(C(R
I-10a)(R
I-10b))
pI-1-,
其中,X
I的每一个亚甲基单元不被替代;或X
I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy
I-2-、-N(R
I-10c)C(O)-、-C(O)N(R
I-10c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR
I-
10c-、-O-、-S-、-SO-、-SO
2-、-P(R
I-10c)-、-P(=O)(R
I-10c)-、-N(R
I-10c)SO
2-、-SO
2N(R
I-10c)-、-C(=S)-、-C(=NR
I-10c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N
2)-,其中,每一个Cy
I-2各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个Cy
I-2各自独立地不被取代,或每一个Cy
I-2各自独立地被至少1个R
I-10c取代;
其中,每一个R
I-10a、R
I-10b和R
I-10c各自独立地不存在,或每一个R
I-10a、R
I-10b和R
I-10c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OR
I-11、-SR
I-11、-N(R
I-
11a)(R
I-11b)、-C(O)R
I-11、-C(=O)OR
I-11、-C(O)C(O)R
I-11、-C(O)CH
2C(O)R
I-11、-S(O)R
I-11、-S(O)
2R
I-
11、-C(O)N(R
I-11a)(R
I-11b)、-SO
2N(R
I-11a)(R
I-11b)、-OC(O)R
I-11、和-N(R
I-11)SO
2R
I-11;或每一个R
I-
10a、R
I-10b和R
I-10c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R
I-10a、R
I-10b和R
I-10c各自独立地不被取代,或每一个R
I-10a、R
I-10b和R
I-10c各自独立地被至少1个R
I-11取代;或每一个R
I-10a和R
I-10b各自独立地与它们之间的原子一起形成选自以下组的环C
I:脂环基、杂环基、芳基和杂芳基,其中每一个环C
I各自独立地不被取代,或每一个环C
I各自独立地被至少1个R
I-11取代;
其中,每一个R
I-11,R
I-11a和R
I-11b各自独立地不存在,或每一个R
I-11,R
I-11a和R
I-11b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,pI-1至少为0。
在一种实施方式中,其中,pI-1选自以下组:0、1、2、3、4和5。
在一种实施方式中,其中,每一个R
I-10a、R
I-10b和R
I-10c各自独立地选自以下组:氢、=O、-OR
I-11、-C(O)R
I-11、烷基和被至少1个R
I-11取代的烷基。
在一种实施方式中,其中,每一个R
I-10a、R
I-10b和R
I-10c各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-10a、R
I-10b和R
I-10c各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个R
I-11,R
I-11a和R
I-11b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-11,R
I-11a和R
I-11b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,X
I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R
I-10c)C(O)-、-C(O)N(R
I-10c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR
I-10c-、-S-和-O-。
在一种实施方式中,其中,X
I的1或2个亚甲基单元各自独立地被选自以下组的基团替代:-C(O)N(R
I-10c)-、-S-、-C(O)-、-OC(O)-、-C(O)O-、和-NR
I-10c-。
在一种实施方式中,其中,X
I选自以下组:-C(O)-、-OC(O)-、-C(O)O-、-NR
I-10c-和-C(O)-NH-CH
2-C(R
I-10a)(R
I-10b)-S-,每一个R
I-10a、R
I-10b和R
I-10c各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,X
I选自以下组:-C(O)-和-C(O)-NH-CH
2-C(CH
3)
2-S-。
在一种实施方式中,其中,L
I-2还包含-B
I-,
其中,L
I-p为三价残基,PEG
I包含聚乙二醇单元,pI-2至少为0。
在一种实施方式中,其中,pI-2选自以下组:0、1、2、3、4和5。
在一种实施方式中,其中L
I-p选自以下组:氨基酸、氨基醇、氨基醛和多胺。
在一种实施方式中,其中L
I-p选自以下组:天冬氨酸、谷氨酸、组氨酸、赖氨酸,精氨酸,丝氨酸,半胱氨酸,苏氨酸,和酪氨酸。
在一种实施方式中,其中L
I-p选自以下组:天冬氨酸,谷氨酸和赖氨酸。
在一种实施方式中,其中L
I-p为:
其中,每一个R
I-12a和R
I-12b各自独立地不存在,或每一个R
I-12a和R
I-12b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
B
I-p选自以下组:-NH-、-N(CH
3)-、-C(O)-、和-O-;
其中,pI-p至少为0。
在一种实施方式中,其中,pI-p选自以下组:0、1、2、3和4。
在一种实施方式中,其中,每一个R
I-12a和R
I-12b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-12a和R
I-12b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中L
I-p选自以下组:
在一种实施方式中,其中,PEG
I包含-(PX
I-(CH
2CH
2O)
pI-3)
pI-4-,其中,pI-3和pI-4各自独立地至少为1,
其中,PX
I包含-(C(R
I-13a)(R
I-13b))
pI-5-,
其中,PX
I的每一个亚甲基单元不被替代,或PX
I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy
I-3-、-N(R
I-13c)C(O)-、-C(O)N(R
I-13c)-、-C(O)-、-OC(O)-、-C(O)O-、 -NR
I-13c-、-O-、-S-、-SO-、-SO
2-、-P(R
I-13c)-、-P(=O)(R
I-13c)-、-N(R
I-13c)SO
2-、-SO
2N(R
I-13c)-、-C(=S)-、-C(=NR
I-13c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N
2)-,其中,每一个-Cy
I-
3-各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个-Cy
I-3-各自独立地不被取代,或每一个-Cy
I-3-各自独立地被至少1个R
I-13c取代;
其中,每一个R
I-13a、R
I-13b和R
I-13c各自独立地不存在;或每一个R
I-13a、R
I-13b和R
I-13c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OR
I-14、-SR
I-14、-N(R
I-
14a)(R
I-14b)、-C(O)R
I-14、-C(=O)OR
I-14、-C(O)C(O)R
I-14、-C(O)CH
2C(O)R
I-14、-S(O)R
I-14、-S(O)
2R
I-
14、-C(O)N(R
I-14a)(R
I-14b)、-SO
2N(R
I-14a)(R
I-14b)、-OC(O)R
I-14、和-N(R
I-14)SO
2R
I-14;或每一个R
I-
13a、R
I-13b和R
I-13c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R
I-13a、R
I-13b和R
I-13c各自独立地不被取代,或每一个R
I-13a、R
I-13b和R
I-13c各自独立地被至少1个R
I-14取代;或每一个R
I-13a和R
I-13b各自独立地与它们之间的原子一起形成选自以下组的环D
I:脂环基、杂环基、芳基和杂芳基,其中每一个环D
I各自独立地不被取代,或每一个环D
I各自独立地被至少1个R
I-14取代;
其中,每一个R
I-14,R
I-14a和R
I-14b各自独立地不存在,或每一个R
I-14,R
I-14a和R
I-14b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,pI-5至少为0。
在一种实施方式中,其中,pI-5选自以下组:0、1、2、3、4和5。
在一种实施方式中,其中,每一个R
I-13a、R
I-13b和R
I-13c各自独立地选自以下组:氢、=O、-OR
I-14、-C(O)R
I-14、烷基和被至少1个R
I-14取代的烷基。
在一种实施方式中,其中,每一个R
I-13a、R
I-13b和R
I-13c各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-13a、R
I-13b和R
I-13c各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个R
I-14,R
I-14a和R
I-14b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-14,R
I-14a和R
I-14b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,PX
I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R
I-13c)C(O)-、-C(O)N(R
I-13c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR
I-13c-、和-O-。
在一种实施方式中,其中,PX
I的1或2个亚甲基单元各自独立地被选自以下组的基团替代:-C(O)-、-OC(O)-、-C(O)O-、和-NR
I-13c-。
在一种实施方式中,其中,PX
I选自以下组:-C(O)-和-NR
I-13c-。
在一种实施方式中,其中,PX
I选自以下组:-C(O)-和-NH-。
在一种实施方式中,其中,pI-3选自以下组:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、和24。
在一种实施方式中,其中,pI-3选自以下组:4、6、8、10、12和24。
在一种实施方式中,其中,pI-3选自以下组:8、9、10、12和24。
在一种实施方式中,其中,pI-4选自以下组:1、2、3、4和5。
在一种实施方式中,其中,PEG
I还包含-PZ
I,PZ
I不存在,或PZ
I选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OR
I-15、-SR
I-15、-N(R
I-15a)(R
I-15b)、-C(O)R
I-15、-C(=O)OR
I-
15、-C(O)C(O)R
I-15、-C(O)CH
2C(O)R
I-15、-S(O)R
I-15、-S(O)
2R
I-15、-C(O)N(R
I-15a)(R
I-15b)、-SO
2N(R
I-
15a)(R
I-15b)、-OC(O)R
I-15、和-N(R
I-15)SO
2R
I-15;或PZ
I选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中PZ
I不被取代,或PZ
I被至少1个R
I-15取代;
其中,每一个R
I-15,R
I-15a和R
I-15b各自独立地不存在,或每一个R
I-15,R
I-15a和R
I-15b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
在一种实施方式中,其中,PZ
I选自以下组:氢、烷基和被至少1个R
I-15取代的烷基。
在一种实施方式中,其中,PZ
I选自以下组:氢、C
1-C
6烷基和被至少1个R
I-15取代的C
1-C
6烷基。
在一种实施方式中,其中,R
I-15选自以下组:-OH、-C(O)H、-NH
2、和-C(=O)OH。
在一种实施方式中,其中,PZ
I选自以下组:氢、-CH
2-CH
2-C(O)OH和甲基。
在一种实施方式中,其中,PEG
I选自以下组:
在一种实施方式中,其中,B
I选自以下组:
在一种实施方式中,其中,L
I-2还包含-Y
I-,
Y
I为-(OCH
2CH
2)
pI-6-O
pI-7-,pI-6和pI-7各自独立地至少为0。
在一种实施方式中,其中,pI-7选自以下组:0和1。
在一种实施方式中,其中,pI-6选自以下组:0、1、2、3、4、5、6、7、8、9、10、11和12。
在一种实施方式中,其中,pI-6选自以下组:3、4、5、6、8、10和12。
在一种实施方式中,其中,pI-6选自以下组:3、4、5、6、7和8。
在一种实施方式中,其中,pI-6选自以下组:3、5和7。
在一种实施方式中,其中,Y
I选自以下组:-(OCH
2CH
2)
3-、-(OCH
2CH
2)
4-、-(OCH
2CH
2)
5-、-(OCH
2CH
2)
6-、-(OCH
2CH
2)
7-和-(OCH
2CH
2)
8-。
在一种实施方式中,其中,Y
I选自以下组:-(OCH
2CH
2)
3-、-(OCH
2CH
2)
5-和-(OCH
2CH
2)
7-。
在一种实施方式中,其中,L
I-2还包含-Z
I-,
Z
I为-(C(R
I-16a)(R
I-16b))
pI-8-,
其中,Z
I的每一个亚甲基单元不被替代;或Z
I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy
I-4-、-N(R
I-16c)C(O)-、-C(O)N(R
I-16c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR
I-
16c-、-O-、-S-、-SO-、-SO
2-、-P(R
I-16c)-、-P(=O)(R
I-16c)-、-N(R
I-16c)SO
2-、-SO
2N(R
I-16c)-、-C(=S)-、-C(=NR
I-16c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N
2)-,其中,每一个Cy
I-4各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个Cy
I-4各自独立地不被取代,或每一个Cy
I-4各自独立地被至少1个R
I-16c取代;
其中,每一个R
I-16a、R
I-16b和R
I-16c各自独立地不存在;或每一个R
I-16a、R
I-16b和R
I-16c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OR
I-17、-SR
I-17、-N(R
I-
17a)(R
I-17b)、-C(O)R
I-17、-C(=O)OR
I-17、-C(O)C(O)R
I-17、-C(O)CH
2C(O)R
I-17、-S(O)R
I-17、-S(O)
2R
I-
17、-C(O)N(R
I-17a)(R
I-17b)、-SO
2N(R
I-17a)(R
I-17b)、-OC(O)R
I-17、和-N(R
I-17)SO
2R
I-17;或每一个R
I-
16a、R
I-16b和R
I-16c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R
I-16a、R
I-16b和R
I-16c各自独立地不被取代,或每一个R
I-16a、R
I-16b和R
I-16c各自独立地被至少1个R
I-17取代;或每一个R
I-16a和R
I-16b各自独立地与它们之间的原子一起形成选自以下组的环E
I:脂环基、杂环基、芳基和杂芳基,其中每一个环E
I各自独立地不被取代,或每一个环E
I各自独立地被至少1个R
I-17取代;
其中,每一个R
I-17,R
I-17a和R
I-17b各自独立地不存在,或每一个R
I-17,R
I-17a和R
I-17b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、=O、=S、-OH、-SH、-NH
2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中,pI-8至少为0。
在一种实施方式中,其中,pI-8选自以下组:0、1、2、3、4、5、6和7。
在一种实施方式中,其中,每一个R
I-16a、R
I-16b和R
I-16c各自独立地选自以下组:氢、=O、-OR
I-17、-C(O)R
I-17、烷基和被至少1个R
I-17取代的烷基。
在一种实施方式中,其中,每一个R
I-16a、R
I-16b和R
I-16c各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-16a、R
I-16b和R
I-16c各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,每一个R
I-17,R
I-17a和R
I-17b各自独立地选自以下组:氢和烷基。
在一种实施方式中,其中,每一个R
I-17,R
I-17a和R
I-17b各自独立地选自以下组:氢和C
1-C
6烷基。
在一种实施方式中,其中,Z
I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R
I-16c)C(O)-、-C(O)N(R
I-16c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR
I-16c-、和-O-。
在一种实施方式中,其中,Z
I的1或2个亚甲基单元各自独立地被选自以下组的基团替代:-C(O)N(R
I-16c)-、-C(O)-、-OC(O)-、-C(O)O-、和-NR
I-16c-。
在一种实施方式中,其中,Z
I选自以下组:-NR
I-16c-、-NR
I-16c-(C(R
I-16a)(R
I-16b))
2-、-(C(R
I-
16a)(R
I-16b))
2、-(C(R
I-16a)(R
I-16b))
5、-(C(R
I-16a)(R
I-16b))
2-C(O)-,-(C(R
I-16a)(R
I-16b))
5-C(O)-,-(C(R
I-
16a)(R
I-16b))
2-C(O)-NR
I-16c-(C(R
I-16a)(R
I-16b))
2-,-(C(R
I-16a)(R
I-16b))
2-NR
I-16c-C(O)-(C(R
I-16a)(R
I-16b))
2-,-C(O)-(C(R
I-16a)(R
I-16b))
2-C(O)-NR
I-16c-(C(R
I-16a)(R
I-16b))
2-和-C(R
I-16a)(R
I-16b)-O-C(O)-NR
I-16c-(C(R
I-
16a)(R
I-16b))
2-。
在一种实施方式中,其中,Z
I选自以下组:-NH-、-(CH
2)
2-,-(CH
2)
5-,(CH
2)
2-C(O)-,-(CH
2)
4-C(O)-,-(CH
2)
5-C(O)-,-(CH
2)
2-C(O)-NH-(CH
2)
2-,-C(O)-(CH
2)
2-C(O)-NH-(CH
2)
2-,-NH-(CH
2)
2-和-CH
2-O-C(O)-NH-(CH
2)
2-。
在一种实施方式中,其中,L
I-2不存在。
在一种实施方式中,其中,L
I-2包含-Z
I-X
I-、-Z
I-或-X
I-。
在一种实施方式中,其中,L
I-2包含-Z
I-X
I-。
在一种实施方式中,其中,L
I-2选自以下组:
在一种实施方式中,其中,L
I-2包含-Z
I-Y
I-X
I-、-Z
I-Y
I-、-Y
I-X
I-或-Y
I-。
在一种实施方式中,其中,L
I-2包含-Z
I-Y
I-X
I-。
在一种实施方式中,其中,L
I-2选自以下组:
在一种实施方式中,其中,L
I-2包含-Z
I-B
I-X
I-、-Z
I-B
I-、-B
I-X
I-或-B
I-。
在一种实施方式中,其中,L
I-2包含-Z
I-B
I-或-B
I-。
在一种实施方式中,其中,L
I-2选自以下组:
在一种实施方式中,其中,L
I还包含L
I-3,L
I-3为多肽残基。
在一种实施方式中,其中L
I-3包含至少1个氨基酸残基。
在一种实施方式中,其中L
I-3包含选自以下组的疏水氨基酸的残基:苯丙氨酸(F),异亮氨酸(I),亮氨酸(L),色氨酸(W),缬氨酸(V),甲硫氨酸(M),酪氨酸(Y),丙氨酸(A),苏氨酸(T),和组氨酸(H)。
在一种实施方式中,其中L
I-3包含选自以下组的亲水氨基酸的残基:丝氨酸(S),谷氨酰胺(Q),精氨酸(R),赖氨酸(K),天冬酰胺(N),谷氨酸(E),脯氨酸(P),瓜氨酸(C)和天冬氨酸(D)。
在一种实施方式中,其中L
I-3包含甘氨酸(G)。
在一种实施方式中,其中L
I-3不包含亲水氨基酸的残基。
在一种实施方式中,其中L
I-3包含选自以下组的氨基酸的残基:甘氨酸(G)、缬氨酸(V)、丙氨酸(A)和苯丙氨酸(F)。
在一种实施方式中,其中L
I-3选自以下组:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)、甘氨酸-甘氨酸-丙氨酸-甘氨酸(GGAG)、丙氨酸-丙氨酸-丙氨酸-甘氨酸(AAAG)、甘氨酸-甘氨酸-甘氨酸-甘氨酸(GGGG)、甘氨酸-甘氨酸-丙氨酸(GGA)、甘氨酸-丙氨酸-甘氨酸(GAG)、甘氨酸-苯丙氨酸-甘氨酸(GFG)、缬氨酸-丙氨酸-甘氨酸(VAG)、丙氨酸-丙氨酸-甘氨酸(AAG)、丙氨酸-丙氨酸-丙氨酸(AAA)、缬氨酸-丙氨酸(VA)、丙氨酸-丙氨酸(AA)、甘氨酸-丙氨酸(GA)、和丙氨酸-甘氨酸(AG)。
在一种实施方式中,其中L
I-3选自以下组:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)和丙氨酸-丙氨酸(AA)。
在一种实施方式中,其中L
I-3包含至少1个亲水氨基酸的残基。
在一种实施方式中,其中L
I-3包含选自以下组的氨基酸的残基:甘氨酸(G)、缬氨酸(V)、丙氨酸(A)、瓜氨酸(C)、赖氨酸(K)、谷氨酸(E)和天冬氨酸(D)。
在一种实施方式中,其中L
I-3选自以下组:谷氨酸-丙氨酸-甘氨酸-甘氨酸(EAGG)、甘氨酸-谷氨酸-丙氨酸-甘氨酸(GEAG)、甘氨酸-天冬氨酸-丙氨酸-甘氨酸(GDAG)、甘氨酸-天冬氨酸-甘氨酸-甘氨酸(GDGG)、甘氨酸-谷氨酸-甘氨酸-甘氨酸(GEGG)、谷氨酸-甘氨酸-甘氨酸(EGG)、谷氨酸-丙氨酸-甘氨酸(EAG)、天冬氨酸-丙氨酸-甘氨酸(DAG)、天冬氨酸-甘氨酸-甘氨酸(DGG)、缬氨酸-赖氨酸-甘氨酸(VKG)、甘氨酸-天冬氨酸-甘氨酸(GDG)、甘氨酸-天冬氨酸-丙氨酸(GDA)、甘氨酸-谷氨酸-甘氨酸(GEG)、缬氨酸-瓜氨酸-甘氨酸(VCG)、甘氨酸-谷氨酸-丙氨酸(GEA)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)、缬氨酸-瓜氨酸(VC)、甘氨酸-谷氨酸(GE)、天冬氨酸-甘氨酸(DG)、天冬氨酸-丙氨酸(DA)、 甘氨酸-天冬氨酸(GD)和缬氨酸-赖氨酸(VK)。
在一种实施方式中,其中L
I-3选自以下组:甘氨酸-谷氨酸-甘氨酸(GEG)、谷氨酸-丙氨酸-甘氨酸(EAG)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)和甘氨酸-谷氨酸(GE)。
在一种实施方式中,其中L
I-3不包含疏水氨基酸的残基。
在一种实施方式中,其中L
I-3包含选自以下组的氨基酸的残基:甘氨酸(G)、谷氨酸(E)和天冬氨酸(D)。
在一种实施方式中,其中L
I-3选自以下组:甘氨酸-谷氨酸(GE)、甘氨酸-甘氨酸(GG)、天冬氨酸-甘氨酸(DG)、甘氨酸-天冬氨酸(GD)、谷氨酸-甘氨酸(EG)、甘氨酸-天冬氨酸-甘氨酸(GDG)、天冬氨酸-甘氨酸-甘氨酸(DGG)、甘氨酸-谷氨酸-甘氨酸(GEG)和甘氨酸-天冬氨酸-甘氨酸-甘氨酸(GDGG)。
在一种实施方式中,其中L
I-3选自以下组:谷氨酸-甘氨酸(EG)、谷氨酸-丙氨酸(EA)、甘氨酸-谷氨酸(GE)、缬氨酸-瓜氨酸(VC)、缬氨酸-丙氨酸(VA)、丙氨酸-丙氨酸(AA)、谷氨酸-丙氨酸-甘氨酸(EAG)、谷氨酸-甘氨酸-甘氨酸(EGG)、甘氨酸-谷氨酸-甘氨酸(GEG)、丙氨酸-丙氨酸-甘氨酸(AAG)、丙氨酸-丙氨酸-丙氨酸(AAA)、缬氨酸-丙氨酸-甘氨酸(VAG)、缬氨酸-瓜氨酸-甘氨酸(VCG)、缬氨酸-赖氨酸-甘氨酸(VKG)、甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)、甘氨酸-甘氨酸-甘氨酸-甘氨酸(GGGG)、甘氨酸-谷氨酸-甘氨酸-甘氨酸(GEGG)、和甘氨酸-谷氨酸-丙氨酸-甘氨酸(GEAG)。
在一种实施方式中,其中L
I-3选自以下组:丙氨酸-丙氨酸(AA)、谷氨酸-丙氨酸-甘氨酸(EAG)、甘氨酸-谷氨酸-甘氨酸(GEG)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)和甘氨酸-谷氨酸(GE)。
另一方面,本申请提供了一种式(I-C)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中:
其中,Ab
I为配体,N
a-I为至少为1的数;
Tr
I为本申请任一项所述的Tr
I,L
I包含L
I-1,L
I-1为二价残基或三价残基,
其中,R
I-G1和R
I-G2各自独立地选自以下组:氢、卤素和烷基,R
I-G3选自以下组:O、S和N。
在一种实施方式中,其中,R
I-G3为O。
在一种实施方式中,其中,R
I-G1为氢,R
I-G2为氢。
在一种实施方式中,其中,L
I为本申请任一项所述的L
I。
在一种实施方式中,其中,Ab
I包含抗体或其抗原结合片段。
在一种实施方式中,其中,所述抗体选自以下组:鼠源抗体、嵌合抗体、人源化抗体和全人源抗体。
在一种实施方式中,其中,所述抗原结合片段选自以下组:Fab,Fab′,Fv片段,F(ab')
2,F(ab)
2,scFv,di-scFv,VHH和dAb。
在一种实施方式中,其中,Ab
I靶向选自以下组的靶点:
AXL,BAFFR,BCMA,BCR–列表组分(BCR–list components),BDCA2,BDCA4,BTLA,BTNL2BTNL3,BTNL8,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CD11c,CD137,CD138,CD14,CD163,CD168,CD 177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,CD40,CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68, CD69,CD70,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90.2,CD96,CLEC12A,CLEC12B,CLEC7A,CLEC9A,CR1,CR3,CRTAM,CSF1R,CTLA4,CXCR1/2,CXCR4,CXCR5,DDR1,DDR2,DEC-205,DLL4,DR6,FAP,FCamR,FCMR,FcR’s,Fire,GITR,HHLA2,II型HLA(HLA class II),HVEM,ICOSLG,IFNAR,IFNLR1,IL10R1,IL10R2,IL12R,IL13RA1,IL13RA2,IL15R,IL17RA,IL17RB,IL17RC,IL17RE,IL20R1,IL20R2,IL21R,IL22R1,IL22RA,IL23R,IL27R,IL29R,IL2Rg,IL31R,IL36R,IL3RA,IL4R,IL6R,IL5R,IL7R,IL9R,整合素(Integrins),LAG3,LIFR,MAG/Siglec-4(唾液酸结合性免疫球蛋白样凝集素-4),MMR,MSR1,NCR3LG1,NKG2D,NKp30,NKp46,OX40(CD134),PDCD1,PROKR1,PVR,PVRIG,PVRL2,PVRL3,RELT,SIGIRR,Siglec-1(唾液酸结合性免疫球蛋白样凝集素-1),Siglec-10,Siglec-5,Siglec-6,Siglec-7,Siglec-8,Siglec-9,SIRPA,SLAMF7,TACI,TCR–列表组分/assoc(TCR-listcomponents/assoc),PTCRA,TCRb,CD3z,CD3,TEK,TGFBR1,TGFBR2,TGFBR3,TIGIT,TLR2,TLR4,TNFα,TROY,TSLPR,TYRO,VLDLR,VSIG4,IL2R-y和VTCN1。
另一方面,本申请提供了一种式(I-D)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中:
其中,Tr
I为本申请任一项所述的Tr
I,L
I-x包含L
I-1x,L
I-1x为连接体,
其中,R
I-G1和R
I-G2各自独立地选自以下组:氢、卤素和烷基,R
I-G3选自以下组:O、S和N。
在一种实施方式中,其中,R
I-G3为O。
在一种实施方式中,其中,R
I-G1为氢,R
I-G2为氢。
在一种实施方式中,其中,L
I-1x选自以下组:能够与氨基偶联的基团、能够与巯基偶联的基团和点击化学基团。
在一种实施方式中,其中,L
I-1x选自以下组:
在一种实施方式中,其中,L
I-1x选自以下组:
其中每一个R
I-L1a,R
I-L1b和R
I-L1c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
在一种实施方式中,其中,L
I-1x选自以下组:
在一种实施方式中,L
I-x还包含L
I-2,L
I-2为本申请任一项所述的L
I-2。
在一种实施方式中,L
I-x还包含L
I-3,L
I-3为本申请任一项所述的L
I-3。
另一方面,本申请提供了一种式(I-E)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中:
其中,Tr
I为本申请任一项所述的Tr
I,
其中,R
I-G1和R
I-G2各自独立地选自以下组:氢、卤素和烷基,R
I-G3选自以下组:O、S和N。
在一种实施方式中,其中,R
I-G3为O。
在一种实施方式中,其中,R
I-G1为氢,R
I-G2为氢。
一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,
其中,所述化合物包含选自以下组的结构:
其中,R
I-p选自以下组:H,-CH
3、-CH-(CH
3)
2、-CH
2-CH(CH
3)
2、-CH(CH
3)-CH
2-CH
3、-CH
2-C
6H
5、-C
8NH
6、-CH
2-C
6H
4-OH、-CH
2-COOH、-CH
2-CONH
2、-(CH
2)
2-COOH、-(CH
2)
4-NH
2、-(CH
2)
2-CONH
2、-(CH
2)
2-S-CH
3、-CH
2-OH、-CH(CH
3)-OH、-CH
2-SH、-C
3H
6、-CH
2-C
3H
3N、-(CH
2)
3-NHC(NH)NH
2和-(CH
2)
3-NHCONH
2。
制备本申请式(I-A)、式(I-B)或式(I-C)所示的任一项所述的化合物或其互变异构体、 内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的方法,其包含以下步骤:在适于在配体和化合物之间形成键的条件下,使所述配体与本申请式(I-D)所示的任一项所述的化合物接触。
一种药物组合物,其含有本申请任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,以及任选地药学上可接受的载体。
一种影响免疫系统功能的方法,包括向受试者施用本申请任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,或本申请任一项所述的药物组合物。
根据本申请任一项所述的方法,所述影响免疫系统功能包含影响免疫细胞的功能。
根据本申请任一项所述的方法,所述免疫细胞选自以下组:颗粒白细胞和无颗粒白细胞。
根据本申请任一项所述的方法,所述免疫细胞选自以下组:中性粒细胞、嗜酸性粒细胞、和嗜碱性粒细胞。
根据本申请任一项所述的方法,所述免疫细胞选自以下组:淋巴细胞和吞噬细胞。
根据本申请任一项所述的方法,所述免疫细胞选自以下组:B细胞、T细胞、自然杀伤细胞、单核细胞、巨噬细胞、肥大细胞和树突状细胞。
本申请任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐和/或本申请任一项所述的药物组合物在制备药物中的应用,所述药物用于预防和/或治疗疾病和/或症状。
根据本申请任一项所述的用途,所述疾病和/或症状包含与糖皮质激素受体信号转导相关的疾病和/或症状。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:增生性疾病和/或症状、代谢性疾病和/或症状、炎症疾病和/或症状和神经退行性疾病和/或症状。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:系统性自身免疫疾病和/或症状、血液系统相关疾病和/或症状、神经肌肉系统相关疾病和/或症状、消化系统相关疾病和/或症状、泌尿系统相关疾病和/或症状、内分泌腺系统相关疾病和/或症状、皮肤肌肉系统相关疾病和/或症状、和呼吸系统系统相关疾病和/或症状。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:类风湿关节炎、系统性红斑狼疮、硬皮病、干燥综合症、强直性脊柱炎、韦格纳肉芽肿病和系统性硬化。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:自身免疫性溶血性贫血、恶性贫血、特发性血小板减少性紫癜、特发性血小板减少症和血管炎。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:多发性硬化、重症肌无力和古兰巴雷综症。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:溃疡性结肠炎、克隆恩病、自身免疫性肝病和萎缩性胃炎。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:IgA肾病、原发性肾病综合征、自身免疫性肾小球肾炎、肺肾出血综合征和狼疮肾炎。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:I型糖尿病、Grave's病、桥本甲状腺炎、原发性肾上腺皮质萎缩和慢性甲状腺炎。
根据本申请任一项所述的用途,所述疾病和/或症状选自以下组:银屑病、寻常型天孢疹、皮肤红斑狼疮、皮肌炎和风湿性多肌痛。
根据本申请任一项所述的用途,所述疾病和/或症状为哮喘。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的说明书中的描述仅仅是示例性的,而非为限制性的。
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下:
图1显示的是本申请ADC-I-743-1对于IL-10细胞因子的释放抑制结果图。
图2A-2B显示的是本申请ADC-I-743-1对于IL-1β细胞因子的释放抑制结果图。
图3显示的是本申请ADC-I-16-2对于IL-10细胞因子的释放抑制结果图。
图4显示的是本申请ADC减少耳朵肿胀的结果图。
图5显示的是本申请ADC降低小鼠爪肿胀的结果图。
图6A和图6B显示的是本申请ADC抑制人外周血单核细胞受R848刺激释放细胞因子的结果图。
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中,术语“配体”通常指能识别和结合目标细胞相关的抗原或受体的大分子化合物。配体的作用可以是将药物呈递给与配体结合的目标细胞群,这些配体包括但不限于蛋白类激素、凝集素、生长因子、抗体或其他能与细胞、受体和/或抗原结合的分子。在本申请中,配体可以表示为Ab,配体抗原通过配体上的杂原子与连接单元形成连接键,可以为抗体或其抗原结合片段,所述抗体可以选自嵌合抗体、人源化抗体、全人抗体或鼠源抗体;所述抗体可以是单克隆抗体。例如所述抗体可以是,靶向以下靶点的抗体或其抗原结合片段:AXL,BAFFR,BCMA,BCR–列表组分(BCR–list components),BDCA2,BDCA4,BTLA,BTNL2BTNL3,BTNL8,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CDllc,CD137,CD138,CD14,CD163,CD168,CD177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,CD40,CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68,CD69,CD70,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90.2,CD96,CLEC12A,CLEC12B,CLEC7A,CLEC9A,CR1,CR3,CRTAM,CSF1R,CTLA4,CXCR1/2,CXCR4,CXCR5,DDR1,DDR2,DEC-205,DLL4,DR6,FAP,FCamR,FCMR,FcR’s,Fire,GITR,HHLA2,II型HLA(HLA class II),HVEM,ICOSLG,IFNAR,IFNLR1,IL10R1,IL10R2,IL12R,IL13RA1,IL13RA2,IL15R,IL17RA,IL17RB,IL17RC,IL17RE,IL20R1,IL20R2,IL21R,IL22R1,IL22RA,IL23R,IL27R,IL29R,IL2Rg,IL31R,IL36R,IL3RA,IL4R,IL6R,IL5R,IL7R,IL9R,整合素(Integrins),LAG3,LIFR,MAG/Siglec-4(唾液酸结合性免疫球蛋白样凝集素-4),MMR,MSR1,NCR3LG1,NKG2D,NKp30,NKp46,OX40(CD134),PDCD1,PROKR1,PVR,PVRIG,PVRL2,PVRL3,RELT,SIGIRR,Siglec-1(唾液酸结合性免疫球蛋白样凝集素-1),Siglec-10,Siglec-5,Siglec-6,Siglec-7,Siglec-8,Siglec-9,SIRPA,SLAMF7,TACI,TCR–列表组分/assoc(TCR-listcomponents/assoc),PTCRA,TCRb,CD3z,CD3,TEK,TGFBR1,TGFBR2,TGFBR3,TIGIT,TLR2,TLR4,TNFα,TROY,TSLPR,TYRO,VLDLR,VSIG4,IL2R-y和VTCN1。
在本申请中,术语“连接体”通常指指一端与配体连接而另一端与药物相连的化学结构片 段或键,也可以连接其他连接体后再与药物和/或配体相连。所述直接或间接连接配体可以是指所述基团通过共价键直接连接配体,也可以是通过连接体连接配体。例如,连接体可以是本申请所述的Tr
I、或-(SP
I-1)
nI-1-所示的结构。例如,可以使用包含酸不稳定接头结构(例如腙)、蛋白酶敏感(例如肽酶敏感)接头结构、光不稳定接头结构、二甲基接头结构、或含二硫化物接头结构的化学结构片段或键作为连接体。
在本申请中,术语某个结构“任选地与其它分子部分相连接”通常是指该结构可以不与任何其它化学结构相连接,或者该结构也可以与一个或多个不同于该结构的其它化学结构(例如本申请所述的配体)相连接(例如,通过化学键连接、或通过连接体连接)。
在本申请中,术语“配体-药物偶联物”通常是指配体通过稳定的连接单元与具有生物活性的药物相连。在本申请中“配体-药物偶联物”可以为抗体-药物偶联物(antibody drug conjugate,ADC),所述ADC可以是指把单克隆抗体或者抗体片段通过稳定的连接单元与具有生物活性的药物相连。例如,所述药物可以是免疫抑制药物。例如,所述药物可以是环索奈德(CAS编号:161115-59-9)。
在本申请中,术语“抗体或其抗原结合片段”通常是指免疫学上的结合试剂和/或来自所有物种的所有抗体,包括二聚体、三聚体和多聚体抗体;双特异性抗体;嵌合抗体;全人源抗体;人源化抗体;重组和改造的抗体以及它们的片段。术语“抗体或其抗原结合片段”可以指具有抗原结合区的任意抗体样分子,该术语包括小分子物质片段如Fab′、Fab、F(ab′)
2、单结构域抗体(DABs)、Fv、scFv(单链Fv)、线性抗体、双抗体等等。术语“抗原结合片段”可以指抗体的保持特异性结合抗原的能力的一个或多个片段。例如,可利用全长抗体的片段来进行抗体的抗原结合功能。制备和使用各种基于抗体的构建物和片段的技术在本领域中是公知的。所述抗体或其抗原结合片段可以包括靶向以下靶点的抗体或其抗原结合片段:AXL,BAFFR,BCMA,BCR–列表组分(BCR–list components),BDCA2,BDCA4,BTLA,BTNL2BTNL3,BTNL8,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CDllc,CD137,CD138,CD14,CD163,CD168,CD177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,CD40,CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68,CD69,CD70,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90.2,CD96,CLEC12A,CLEC12B,CLEC7A,CLEC9A,CR1,CR3,CRTAM,CSF1R,CTLA4,CXCR1/2,CXCR4,CXCR5,DDR1,DDR2,DEC-205,DLL4,DR6,FAP,FCamR,FCMR,FcR’s,Fire,GITR,HHLA2,II型HLA(HLA class II),HVEM,ICOSLG,IFNAR,IFNLR1,IL10R1,IL10R2,IL12R,IL13RA1,IL13RA2,IL15R,IL17RA,IL17RB,IL17RC,IL17RE,IL20R1,IL20R2,IL21R,IL22R1,IL22RA,IL23R,IL27R,IL29R,IL2Rg,IL31R,IL36R,IL3RA,IL4R,IL6R,IL5R,IL7R,IL9R,整合素(Integrins),LAG3,LIFR,MAG/Siglec-4(唾液酸结合性免疫球蛋白样凝集素-4),MMR,MSR1,NCR3LG1,NKG2D,NKp30,NKp46,OX40(CD134),PDCD1,PROKR1,PVR,PVRIG,PVRL2,PVRL3,RELT,SIGIRR,Siglec-1(唾液酸结合性免疫球蛋白样凝集素-1),Siglec-10,Siglec-5,Siglec-6,Siglec-7,Siglec-8,Siglec-9,SIRPA,SLAMF7,TACI,TCR–列表组分/assoc(TCR-listcomponents/assoc),PTCRA,TCRb,CD3z,CD3,TEK,TGFBR1,TGFBR2,TGFBR3,TIGIT,TLR2,TLR4,TNFα,TROY,TSLPR,TYRO,VLDLR,VSIG4,IL2R-y和VTCN1。
在本申请中,术语“BDCA2”通常是指一种Ⅱ型C型凝集素。本申请的BDCA2通常可以包含血液树突细胞抗原2(Blood Dendritic Cells Antigen 2)、其变体以及其功能活性片段。以BDCA-2为靶分子可以靶向树突细胞的炎症环境。例如,BDCA2在UniProt中的登录号可以是Q8WTT0。
在本申请中,术语“TNFα”通常是指一种细胞因子,例如肿瘤坏死因子-α。本申请的TNFα通常可以包含肿瘤坏死因子-α、其变体以及其功能活性片段。以TNFα为靶分子可以靶向炎症环境。例如,TNFα在UniProt中的登录号可以是P01375。
在本申请中,术语“CD40”通常是指肿瘤坏死因子(TNF)受体家族的50-55kDa跨膜糖蛋白。本申请的CD40通常可以包含CD40、其变体以及其功能活性片段。以CD40为靶分子可以靶向B细胞的炎症环境。例如,CD40在UniProt中的登录号可以是A0A0S2Z3C7。
在本申请中,术语“IFNAR”通常是指干扰素受体。本申请的IFNAR通常可以包含干扰素受体、其变体以及其功能活性片段。以IFNAR为靶分子可以靶向免疫细胞的炎症环境。例如,IFNAR在UniProt中的登录号可以是P17181。
在本申请中,术语“嵌合抗体(chimeric antibody)”通常是指鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体,可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体,可以建立分泌鼠源性特异性单抗的杂交瘤,然后从鼠杂交瘤细胞中克隆可变区基因,可以根据需要克隆人抗体的恒定区基因,将鼠可变区基因与人恒定区基因连接成嵌合基因后插入表达载体中,可以在真核系统或原核系统中表达嵌合抗体分子。
在本申请中,术语“人源化抗体(humanized antibody)”,也称为CDR移植抗体(CDR-grafted antibody),通常是指将鼠的CDR序列移植到人的抗体可变区框架,即不同类型的人种 系抗体框架序列中产生的抗体。可以克服嵌合抗体由于携带大量鼠蛋白成分,从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库。
在本申请中,术语“全人源抗体”、“全人抗体”或“完全人源抗体”,也称“全人源单克隆抗体”,其抗体的可变区和恒定区可以都是人源的,去除免疫原性和毒副作用。单克隆抗体的发展经历了四个阶段,分别为:鼠源性单克隆抗体、嵌合性单克隆抗体、人源化单克隆抗体和全人源单克隆抗体。本申请所述抗体或配体可以为全人源单克隆抗体。全人抗体制备的相关技术可以为:人杂交瘤技术、EBV转化B淋巴细胞技术、噬菌体显示技术(phage display)、转基因小鼠抗体制备技术(transgenic mouse)和单个B细胞抗体制备技术等。
在本申请中,术语“CDR”通常是指抗体的可变结构域内主要促成抗原结合的6个高变区之一。所述6个CDR的最常用的定义之一由Kabat E.A.等人,(1991)Sequences of proteins of immunological interest.NIH Publication 91-3242)提供,Chothia等人,“CanonicalStructures For the Hypervariable Regions of Immunoglobulins,”J.Mol.Biol.196:901(1987);和MacCallum等人,“Antibody-Antigen Interactions:Contact Analysis and Binding Site Topography,”J.Mol.Biol.262:732(1996))。如本申请中使用的,CDR的Kabat定义可以应用于轻链可变结构域的CDR1、CDR2和CDR3(CDR L1、CDR L2、CDR L3或L1、L2、L3),以及重链可变结构域的CDR1、CDR2和CDR3(CDR H1、CDR H2、CDR H3或H1、H2、H3)。
在本申请中,术语“亚甲基”通常是指1个碳原子的基团除去两个氢原子所衍生的残基。亚甲基可以是取代的或非取代的,替代或者非替代的。术语“亚烷基”通常指饱和的直链或支链脂肪族烃基,其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基,其可以为包含1至20个碳原子的直链或支链基团,例如含有1至12个碳原子,例如含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH
2-)、1,1-亚乙基(-CH(CH
3)-)、1,2-亚乙基(-CH
2CH
2)-、1,1-亚丙基(-CH(CH
2CH
3)-)、1,2-亚丙基(-CH
2CH(CH
3)-)、1,3-亚丙基(-CH
2CH
2CH
2-)、1,4-亚丁基(-CH
2CH
2CH
2CH
2-)和1,5-亚丁基(-CH
2CH
2CH
2CH
2CH
2-)等。亚烷基可以是取代的或非取代的,替代或者非替代的,例如当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基可以独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代,例如可以是氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、 -CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、或C
1-6脂肪族基团。亚甲基或亚烷基可以是取代的或非取代的。
在本申请中,术语“芳基”通常是指具有芳环上除去一个氢原子所衍生的残基。术语“芳环”可以指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环),可以为6至10元,例如苯和萘。所述芳环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。芳基可以是取代的或非取代的,当被取代时,取代基可以为一个或多个以下基团,其独立地选自以下组:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、和杂环烷硫基。芳基可以是取代的或非取代的。
在本申请中,术语“杂芳基”通常是指具有从杂芳环的碳原子上除去一个氢原子所衍生的残基。术语“杂芳环”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子可以选自以下组:氧、硫和氮。杂芳基可以为5至10元,可以为5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或非取代的,当被取代时,取代基可以为一个或多个以下基团,其独立地选自以下组:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、和杂环烷硫基。杂芳基可以是取代的或非取代的。
在本申请中,术语“杂环基”通常是指稳定的不具有芳香性的3元-7元单环碳环结构,融合的7元-10元双环杂环结构或桥联的6元-10元双环杂环结构,这些环状结构即可以是饱和的,也可以是部分饱和的,除碳原子外,这些环状结构中还含有一个或多个杂原子,其中杂原子可以选自以下组:氧、硫和氮。例如是含有1-4个上述定义的杂原子。当用来表示杂环环状结构上的原子时,术语“氮”可以包括发生过取代反应的氮。杂环基可以是取代的或非取代的。亚杂环基可以是取代的或非取代的。
在本申请中,术语“杂环烷基”通常是指稳定的不具有芳香性的3元-7元单环烷结构,融合的7元-10元双环杂环结构或桥联的6元-10元双环杂环结构,除碳原子外,这些环状结构中还含有一个或多个杂原子,其中杂原子可以选自以下组:氧、硫和氮。例如是含有1-4个上述定义的杂原子。当用来表示杂环环状结构上的原子时,术语“氮”可以包括发生过取代反应的氮。杂环烷基可以是取代的或非取代的。
在本申请中,术语“脂环基”通常是指具有从脂肪环的相同碳原子或多个不同的碳原子上除去氢原子所衍生的残基。术语“环烷”通常指饱和或部分不饱和单环或多环环状烃,碳环包含3至20个碳原子,可以包含3至12个碳原子,可以包含3至10个碳原子,可以包含3至8个碳原子。脂环基的非限制性实例包括环丙烷基、环丁烷基、环戊烷基、环戊烯基、环己烷基、环己烯基、环己二烯基、环庚烷基、环庚三烯基、环辛烷基等;多环碳环可以包括螺环、稠环和桥环的碳环。脂环基可以是取代的或非取代的。在本申请中,术语“碳环基”通常是指具有碳环的碳原子上除去一个氢原子所衍生的残基。术语“碳环”通常指饱和或部分不饱和单环或多环环状烃,碳环包含3至20个碳原子,可以包含3至12个碳原子,可以包含3至10个碳原子,可以包含3至8个碳原子。单环碳环的非限制性实例包括环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环己二烯、环庚烷、环庚三烯、环辛烷等;多环碳环可以包括螺环、稠环和桥环的碳环。碳环基可以是取代的或非取代的。在某些情形下,脂环和碳环可以相互替代使用。
在本申请中,术语“部分不饱和的”通常是指环状结构中环分子间至少含一个双键或三键。术语“部分不饱和”涵盖带有多处不饱和的环状结构,但并非意在包括本申请所定义的芳环或杂芳环。术语"不饱和的"表示部分具有一个或多个不饱和度。
在本申请中,术语“卤素”通常是指氟、氯、溴、碘,例如可以是氟、氯。
在本申请中,术语“脂肪族基团”通常是指具有1-12个碳原子的直链烃、支链烃或环状结构的烃,这些烃或者是完全饱和烃;或者带有一个或多个不饱和单元,但不饱和单元不是芳香类基团。例如,适用的脂肪族基团可以包括取代的或未取代的直链、支链或环状结构的烷基、烯基、炔基以及这些基团的混合物;比如是(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。例如,脂肪族基团具有1-12、1-8、1-6、1-4或1-3个碳原子。脂肪族基团可以是取代的或非取代的。
在本申请中,术语“烷基”通常是指烷除去氢原子所衍生的残基。烷基可以是取代的或非取代的,替代或者非替代的。术语“烷基”通常指饱和的直链或支链脂肪族烃基,其具有从母体烷的相同碳原子或两个不同的碳原子上除去氢原子所衍生的残基,其可以为包含1至20个碳原子的直链或支链基团,例如含有1至12个碳原子,例如含有1至6个碳原子的链烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丙基、丁基等。烷基可以是取代的或非取代的,替代或者非替代的,例如当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基可以独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、 卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代,例如可以是氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H或C
1-6脂肪族基团。
在本申请中,术语“烯基”通常是指含有一个或多个双键的直链或支链烃基。烯基的示例性实例包括烯丙基、高烯丙基、乙烯基、巴豆基、丁烯基、戊烯基和己烯基。具有一个以上双键的C
2-6链烯基的示例性实例包括丁二烯基、戊二烯基、己二烯基和己三烯基以及它们的支化形式。不饱和键(双键)的位置可以是在碳链的任何一个位置。烯基可以是取代的或非取代的。
在本申请中,术语“炔基”通常是指不饱和直链或支链炔基,例如乙炔基、1-丙炔基、炔丙基、丁炔基等。炔基可以是取代的或非取代的。
在本申请中,术语“三价的”基团或“三价残基”通常是指在所述基团中具有3个键合位置的基团。例如,三价基团包括但不限于三价的链烷基,三价的环烷基,三价的杂环烷基,三价的烯基,三价的炔基,三价的芳基,三价的杂芳基和本申请中的三价连接体。
在本申请中,术语“二价的”基团或“二价残基”通常是指在所述基团中具有2个键合位置的基团。例如,二价基团包括但不限于二价的链烷基,二价的环烷基,二价的杂环烷基,二价的烯基,二价的炔基,二价的芳基,二价的杂芳基和本申请中的二价连接体。
在本申请中,术语“任选”或“任选地”通常意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明可以包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
在本申请中,术语“能够与氨基偶联的基团”通常是指所述化合物A具有氨基,所述化合物B具有能够与氨基偶联的基团,化合物B通过能够与氨基偶联的基团与化合物A的氨基反应,可以以此实现化合物A与化合物B的连接。
在本申请中,术语“能够与巯基偶联的基团”通常是指所述化合物A具有巯基,所述化合物B具有能够与巯基偶联的基团,化合物B通过能够与巯基偶联的基团与化合物A的巯基反应,可以以此实现化合物A与化合物B的连接。
在本申请中,术语“点击化学基团”通常是指能够快速高效偶联的反应基团。例如,点击 化学反应可以包含以下组反应:环加成反应、亲核开环反应、非醇醛的羰基化学和碳碳多键的加成反应。例如,点击化学基团可以选自以下组:
在本申请中,基团X与基团Y的“连接”通常可以处于任一定向,任一定向通常是指在基团X用于连接体Y和基团Z时,所述基团X的两个或更多个连接位点可以任意地与基团Y或基团Z连接。例如,SP
2的-C(O)O-与(SP
1)
n1的-NH-CH
2-连接,可以是SP
2的C原子与(SP
1)
n1的N原子连接,可以是SP
2的O原子与(SP
1)
n1的N原子连接,可以是SP
2的C原子与(SP
1)
n1的原子连接,或可以是SP
2的O原子与(SP
1)
n1的C原子连接。
在本申请中,术语“取代的”通常指基团中的一个或多个氢原子,例如为最多5个,例如为1~3个氢原子彼此独立地被相应数目的取代基取代。取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
在本申请中,术语0个或多个(例如,0个或1个以上、0个或1个、0个)亚甲基单元被“替代”通常指当所述结构包含1个或多个亚甲基单元时,所述一个或多个亚甲基单元可以不被替代,或被一个或多个不是亚甲基的基团(例如-NHC(O)-、-C(O)NH-、-C(O)-、-OC(O)-、-C(O)O-、-NH-、-O-、-S-、-SO-、-SO
2-、-PH-、-P(=O)H-、-NHSO
2-、-SO
2NH-、-C(=S)-、-C(=NH)-、-N=N-、-C=N-、-N=C-或-C(=N
2)-)所替代。
基团中的一个或多个氢原子,例如为最多5个,例如为1~3个氢原子彼此独立地被相应数目的取代基取代。取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
在本申请中,术语“化合物”通常指具有两种或两种以上不同元素的物质。例如,本申请的化合物可以是有机化合物,例如本申请的化合物可以是分子量500以下的化合物,可以是分子量1000以下的化合物,也可以是分子量1000以上的化合物,也可以是10000以上、100000以上的化合物。在本申请中,化合物还可以是指通过化学键相连的化合物,例如可以是一个或多个分子量1000以下的分子通过化学键与生物大分子相连的化合物,所述生物大分 子可以是高聚糖、蛋白、核酸、多肽等。例如本申请的化合物可以包括蛋白质与一个或多个分子量1000以下的分子相连的化合物,可以是包括蛋白质与一个或多个分子量10000以下的分子相连的化合物,可以是包括蛋白质与一个或多个分子量100000以下的分子相连的化合物.
除非另有指明,否则本申请所述的结构还可以包括仅在是否存在一个或多个同位素富集原子方面存在差别的化合物。举例而言,除了氢原子被氘或氚所取代,或碳原子被碳13或1碳14所取代之外,其余部分均与本申请结构一致的化合物均在本申请的范围之内。
在本申请中,术语“亲水氨基酸”通常是指以甘氨酸的亲水性为标准,亲水能力高于甘氨酸的氨基酸可以作为亲水氨基酸。例如,亲水氨基酸可以包含选自以下组的氨基酸:丝氨酸(S),谷氨酰胺(Q),精氨酸(R),赖氨酸(K),天冬酰胺(N),谷氨酸(E),脯氨酸(P),和天冬氨酸(D)。在本申请中,术语“疏水氨基酸”通常是指以甘氨酸的亲水性为标准,亲水能力低于甘氨酸的氨基酸可以作为疏水氨基酸。例如,疏水氨基酸可以包含选自以下组的氨基酸:苯丙氨酸(F),异亮氨酸(I),亮氨酸(L),色氨酸(W),缬氨酸(V),甲硫氨酸(M),酪氨酸(Y),瓜氨酸(C),丙氨酸(A),苏氨酸(T),和组氨酸(H)。例如,甘氨酸作为特殊氨基酸,既不是亲水氨基酸,也不是疏水氨基酸。
在本申请中,术语“药物组合物”通常是指含有一种或多种本申请所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物可以是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。常规的药物组合物的制备可以见中国药典。
在本申请中,术语“药学上可接受的盐”或“可药用盐”通常是指本申请化合物或配体-药物偶联物的盐,或本申请中所述的化合物的盐,这类盐用于哺乳动物体内时可以具有安全性和/或有效性,且可以具有应有的生物活性,本申请抗体-抗体药物偶联化合物可以与酸形成盐,药学上可接受的盐的非限制性实例包括:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、草酸盐、硝酸盐、梨酸盐、磷酸氢盐、磷酸二氢盐、水杨酸盐、柠檬酸氢盐、酒石酸盐、马来酸盐、富马酸盐、甲酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐。
在本申请中,术语“溶剂化物”或“溶剂化合物”通常是指本申请的配体-药物偶联化合物与一种或多种溶剂分子形成可药用的溶剂化物,溶剂分子的非限制性实例包括水、乙醇、乙腈、异丙醇、DMSO、乙酸乙酯、DMA、DMF、甲醇、丙醇、丙三醇、乙二醇、叔丁醇、二氧六环、四氢呋喃。
术语“载药量”通常是指每个配体上加载的药物平均数量,也可以表示为药物和抗体量的比值,药物载量的范围可以是每个配体(Ab)连接0-12个,例如1-10个药物。在本申请的实施方式中,载药量表示为N
a,示例性的可以为1,2,3,4,5,6,7,8,9,10的均值。可用常规方法如UV/可见光光谱法,质谱,ELISA试验和HPLC特征鉴定偶联反应后每个ADC分子的载药量。例如,本申请连接配体的化学键数可以不限于1条,当本申请使用一条横线表示配体与药物连接或者配体与连接体连接时,该条横线可以表示配体与与药物或者连接体的连接是通过一条化学键,如共价键连接的,也可以表示配体与与药物或者连接体的连接是通过两条及以上条化学键,如共价键连接的。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液,例如1,3-丁二醇中制备的溶液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。例如,可使用包括合成甘油单或二酯在内的任何调和固定油。此外,脂肪酸例如油酸也可以制备注射剂。
在本申请中,术语“包含”通常是指包括明确指定的特征,但不排除其他要素。术语“以上”、“以下”通常是指包含本数的情况。
在本申请中,术语“约”通常是指在指定数值以上或以下0.5%-10%的范围内变动,例如在指定数值以上或以下0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、或10%的范围内变动。
在本申请中,本申请的化合物包含化合物的其互变异构体、内消旋体、外消旋体、对映异构体、和/或非对映异构体。在本申请中,术语“非对映异构体”通常是指具有两个或更多个手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体可以具有不同的物理性质,例如、熔点、沸点、波谱性质和反应性。在本申请中,术语“互变异构体”或“互变异构形式”可互换使用,通常是指可通过低能垒(low energy barrier)互相转化的不同能量的结构异构体。例如,质子互变异构体(protontautomer)(也称为质子移变互变异构体(prototropic tautomer))包括通过质子迁移进行的互相转化,诸如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组进行的互相转化。在本申请中,术语“内消旋体”通常是指分子内含有不对称性的原子,但具有对称因素而使分子内总旋光度为零。术语"外消旋体"或"外消旋混合物"是指由等摩尔量的两种对映异构体物质构成的组合物。
在本申请中,本申请的化合物的某些原子可能以一种以上的同位素形式出现。例如,氢可能以氕(
1H)、氘(
2H)和氚(
3H)的形式存在,碳可能以三种不同的同位素(
12C、
13C和
14C)自然存在。可并入本申请化合物中的同位素示例还包括但不限于
15N、
18O、
17O、
18F、
32P、
33P、
129I、
131I、
123I、
124I、
125I,或者类似的同位素。因此,相对于这些同位素的自然丰度,本申请的化合物可富集在一种或多种这些同位素中。如本领域技术人员所知,此类同位素富集化合物可用于多种用途。例如,用重同位素如氘(
2H)替代可能会提供某些治疗优势,这可以是由于更高的代谢稳定性。例如,氘(
2H)的自然丰度约为0.015%。因此,自然界中大约每6500个氢原子,就有一个氘原子。因此,本发明的含氘化合物在一个或多个位置(视情况而定)的氘丰度大于0.015%。
发明详述
化合物
本申请提供一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物可以包含以下表1中的结构:
表1本申请化合物可以包含的结构
其中的脚标N
a-I表示列表中化合物载荷药物的平均数,例如N
a-I可以是大于0的任何数,其中Ab表示列表中化合物的配体部分,Ab可以是本申请中表示的任一种配体。
配体
本申请所述配体可以是蛋白类激素、凝集素、生长因子、抗体或其他能与细胞、受体和/或抗原结合的分子。例如,本申请的配体可以是抗体或其抗原结合片段。
在本申请中,所述配体包含抗体轻链可变区VL中的至少一个CDR。本申请所述CDR可以是根据Kabat定义的;也可以是根据Chothia定义的,各种方式定义的CDR序列均包含在本申请的保护范围之内。
在本申请中,所述抗原结合蛋白可包含LCDR1,且所述LCDR1可包含SEQ ID NO:1-2、21和31中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
在本申请中,所述抗原结合蛋白可包含LCDR2,且所述LCDR2可包含SEQ ID NO:3-4、22和32中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
在本申请中,所述抗原结合蛋白可包含LCDR3,且所述LCDR3可包含SEQ ID NO:5-6、23和33中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
在本申请中,所述分离的抗原结合蛋白可包含LCDR1-3。其中,所述LCDR1包含SEQ ID NO:1-2、21和31中任一项所示的氨基酸序列;所述LCDR2包含SEQ ID NO:3-4、22和32中任一项所示的氨基酸序列;且所述LCDR3包含SEQ ID NO:5-6、23和33中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与BIIB059相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:1所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:3所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:5所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有BDCA2结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Humira相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:2所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:4所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:6所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有TNFα结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Iscalimab相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:21所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:22所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:23所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有CD40结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Anifrolumab相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:31所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:32所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:33所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有IFNAR结合能力。例如,本申请所述的抗原结合蛋白可以具有IFNAR1结合能力。所述CDR可以是根据Kabat定义的。
本申请所述的抗原结合蛋白所述的抗原结合蛋白可包含抗体重链可变区VH中的至少一个CDR。所述CDR可以是根据Kabat定义的。
在本申请中,所述抗原结合蛋白可包含HCDR1,且所述HCDR1可包含SEQ ID NO:7-8、24和34中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
在本申请中,所述抗原结合蛋白可包含HCDR2,且所述HCDR2可包含SEQ ID NO:9-10、25和35中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
在本申请中,所述抗原结合蛋白可包含HCDR3,且所述HCDR3可包含SEQ ID NO:11-12、26和36中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
在本申请中,所述分离的抗原结合蛋白可包含HCDR1-3。其中,所述HCDR1包含SEQ ID NO:7-8、24和34中任一项所示的氨基酸序列;所述HCDR2包含SEQ ID NO:9-10、25和35中任一项所示的氨基酸序列;且所述HCDR3包含SEQ ID NO:11-12、26和36中任一项所示的氨基酸序列。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与BIIB059相同的HCDR1-3,其中,所述HCDR1可包含SEQ ID NO:7所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:9所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:11所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有BDCA2结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Humira相同的HCDR1-3,其中,所述HCDR1可包含SEQ ID NO:8所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:10所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:12所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有TNFα结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Iscalimab相同的HCDR1-3,其中,所述HCDR1可包含SEQ ID NO:24所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:25所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:26所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有CD40结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Anifrolumab相同的HCDR1-3,其中,所述HCDR1可包含SEQ ID NO:34所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:35所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:36所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有IFNAR结合能力。例如,本申请所述的抗原结合蛋白可以具有IFNAR1结合能力。所述CDR可以是根据Kabat定义的。
在本申请中,所述分离的抗原结合蛋白可包含LCDR1-3和HCDR1-3。其中,所述LCDR1包含SEQ ID NO:1-2、21和31中任一项所示的氨基酸序列;所述LCDR2包含SEQ ID NO:3-4、22和32中任一项所示的氨基酸序列;所述LCDR3包含SEQ ID NO:5-6、23和33中任一项所示的氨基酸序列;所述HCDR1包含SEQ ID NO:7-8、24和34中任一项所示的氨基酸序列;所述HCDR2包含SEQ ID NO:9-10、25和35中任一项所示的氨基酸序列;且所述HCDR3包含SEQ ID NO:11-12、26和36中任一项所示的氨基酸序列。所述CDR可以是根 据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与BIIB059相同的LCDR1-3和HCDR1-3。其中,所述LCDR1可包含SEQ ID NO:1所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:3所示的氨基酸序列;所述LCDR3可包含SEQ ID NO:5所示的氨基酸序列;所述HCDR1可包含SEQ ID NO:7所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:9所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:11所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有BDCA2结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Humira相同的LCDR1-3和HCDR1-3。其中,所述LCDR1可包含SEQ ID NO:2所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:4所示的氨基酸序列;所述LCDR3可包含SEQ ID NO:6所示的氨基酸序列;所述HCDR1可包含SEQ ID NO:8所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:10所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:12所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有TNFα结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Iscalimab相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:21所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:22所示的氨基酸序列;所述LCDR3可包含SEQ ID NO:23所示的氨基酸序列;所述HCDR1可包含SEQ ID NO:24所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:25所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:26所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有CD40结合能力。所述CDR可以是根据Kabat定义的。
例如,本申请所述的抗原结合蛋白可包含与Anifrolumab相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:31所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:32所示的氨基酸序列;所述LCDR3可包含SEQ ID NO:33所示的氨基酸序列;所述HCDR1可包含SEQ ID NO:34所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:35所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:36所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有IFNAR结合能力。例如,本申请所述的抗原结合蛋白可以具有IFNAR1结合能力。所述CDR可以是根据Kabat定义的。
在本申请中,所述抗原结合蛋白可包含轻链可变区VL,且所述VL可包含SEQ ID NO:13-14、28和38中任一项所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含重链可变区VH,且所述VH可包含SEQ ID NO: 15-16、27和37中任一项所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含轻链可变区VL和重链可变区VH。其中,所述VL可包含SEQ ID NO:13-14、28和38中任一项所示的氨基酸序列,且所述VH可包含SEQ ID NO:15-16、27和37中任一项所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与BIIB059相同的轻链可变区VL和重链可变区VH。其中,所述VL可包含SEQ ID NO:13所示的氨基酸序列,且所述VH可包含SEQ ID NO:15所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有BDCA2结合能力。
例如,本申请所述的抗原结合蛋白可包含与Humira相同的轻链可变区VL和重链可变区VH。其中,所述VL可包含SEQ ID NO:14所示的氨基酸序列,且所述VH可包含SEQ ID NO:16所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有TNFα结合能力。
例如,本申请所述的抗原结合蛋白可包含与Iscalimab相同的轻链可变区VL和重链可变区VH。其中,所述VL可包含SEQ ID NO:28所示的氨基酸序列,且所述VH可包含SEQ ID NO:27所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有CD40结合能力。
例如,本申请所述的抗原结合蛋白可包含与Anifrolumab相同的轻链可变区VL和重链可变区VH。其中,所述VL可包含SEQ ID NO:38所示的氨基酸序列,且所述VH可包含SEQ ID NO:37所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有IFNAR结合能力。例如,本申请所述的抗原结合蛋白可以具有IFNAR1结合能力。
在本申请中,所述抗原结合蛋白可包含轻链,且所述轻链可包含SEQ ID NO:17-18、29和39中任一项所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含重链,且所述重链可包含SEQ ID NO:19-20、30和40中任一项所示的氨基酸序列。
本申请中,所述抗原结合蛋白可包含抗体轻链和抗体重链,其中,所述轻链可包含SEQ ID NO:17-18、29和39中任一项所示的氨基酸序列,且所述重链可包含SEQ ID NO:19-20、30和40中任一项所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与BIIB059相同的抗体轻链和抗体重链,其中,所述轻链可包含SEQ ID NO:17所示的氨基酸序列,且所述重链可包含SEQ ID NO:19所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有BDCA2结合能力。
例如,本申请所述的抗原结合蛋白可包含与Humira相同的抗体轻链和抗体重链,其中,所述轻链可包含SEQ ID NO:18所示的氨基酸序列,且所述重链可包含SEQ ID NO:20所示 的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有TNFα结合能力。
例如,本申请所述的抗原结合蛋白可包含与Iscalimab相同的抗体轻链和抗体重链,其中,所述轻链可包含SEQ ID NO:29所示的氨基酸序列,且所述重链可包含SEQ ID NO:30所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有CD40结合能力。
例如,本申请所述的抗原结合蛋白可包含与Anifrolumab相同的抗体轻链和抗体重链,其中,所述轻链可包含SEQ ID NO:39所示的氨基酸序列,且所述重链可包含SEQ ID NO:40所示的氨基酸序列。例如,本申请所述的抗原结合蛋白可以具有IFNAR(interferon-α/βreceptor)结合能力。例如,本申请所述的抗原结合蛋白可以具有IFNAR1(interferon-α/βreceptor 1)结合能力。
合成技术方案
为了完成本申请的合成目的,本申请采用了如下的合成技术方案:
方案1
本申请式(I-D)或式(II-D)所示的化合物的制备方法,其可以包含:
第一步:通式(Y1)化合物和通式(Y2)化合物在任选碱性条件下反应,得到通式(Y3);
第二步:通式(P1)化合物和通式(Y4)化合物在任选酸性或碱性条件下反应,得到通式(P2);
第三步:通式(P2)化合物脱除保护基PG,得到通式(P3);
第三步:通式(P3)化合物和通式(Y3)化合物在任选缩合剂存在下,任选在碱性条件下反应,得到式(I-D)所示的化合物;
其中,
AG
1和AG
2为常用羟基、或氨基的活化基团;
PG为常见羟基、氨基或羧基的保护基;
L
3
a与L
3
b可以共同组成本申请任一式(I-D)或式(II-D)所示的化合物所分别定义的L
I-
3或L
II-3;Tr、L
1x、L
2、和L
3可以分别如本申请任一式(I-D)所示的化合物中Tr
I、L
I-1x、L
I-
2、L
I-3所定义,或如本申请任一式(II-D)所示的化合物中Tr
II、L
II-1x、L
II-2、L
II-3所定义;
提供碱性条件的试剂包括有机碱和无机碱,所述的有机碱包括但不限于三乙胺,二乙胺,N-甲基吗啉,吡啶,六氢吡啶,NN-二异丙基乙胺,正丁基锂,二异丙基氨基锂,醋酸钾,叔丁醇钠,叔丁醇钾等;所述无机碱包括但不限于氢化钠,碳酸钾,碳酸钠,碳酸铯,氢氧化钠,氢氧化锂等;
提供酸性条件的试剂包括质子酸和路易斯酸,所述质子酸包括但不限于盐酸,硫酸,硝酸,亚硝酸,亚硫酸,磷酸,亚磷酸,甲酸、乙酸、丙酸、丁酸、柠檬酸、苯甲酸,对甲基苯磺酸,对硝基苯甲酸,甲磺酸,三氟甲磺酸,三氟乙酸;所述路易斯酸包括但不限于三氟化硼,氯化锌,氯化镁,氯化铝,氯化锡,氯化铁;
缩合剂可以选自4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐、1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、0-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、0-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鑰六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷,可以是4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐或1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
方案2
本申请式(I-D)或式(II-D)所示的化合物的制备方法,其可以包含:
第一步:通式(Y1)化合物和通式(Y2)化合物在任选碱性条件下反应,得到通式(Y3);
第二步:通式(P1)化合物和通式(Y4)化合物在任选酸性或碱性条件下反应,得到通式(P2);
第三步:通式(P2)化合物脱除保护基PG
2得到通式(P3);
第三步:通式(P3)化合物和通式(Y3)化合物在任选缩合剂存在下,任选在碱性条件下反应,得到通式(P4);
第四步:通式(P4)化合物脱除保护基PG
1,得到式(I-D)所示的化合物;
其中,
AG
1和AG
2为常用羟基、或氨基或其它基团的活化基团;
PG
1和PG
2为任意氨基、羧基或羟基的保护基;
L
3
a与L
3
b可以共同组成本申请任一式(I-D)或式(II-D)所示的化合物所分别定义的L
I-
3或L
II-3;Tr、L
1x、L
2、L
3可以分别如本申请任一式(I-D)所示的化合物中Tr
I、L
I-1x、L
I-2、L
I-3所定义,或如本申请任一式(II-D)所示的化合物中Tr
II、L
II-1x、L
II-2、L
II-3所定义;
提供碱性条件的试剂包括有机碱和无机碱,所述的有机碱包括但不限于三乙胺,二乙胺,N-甲基吗啉,吡啶,六氢吡啶,NN-二异丙基乙胺,正丁基锂,二异丙基氨基锂,醋酸钾,叔丁醇钠,叔丁醇钾等;所述无机碱包括但不限于氢化钠,碳酸钾,碳酸钠,碳酸铯,氢氧化钠,氢氧化锂等;
提供酸性条件的试剂包括质子酸和路易斯酸,所述质子酸包括但不限于盐酸,硫酸,硝酸,亚硝酸,亚硫酸,磷酸,亚磷酸,甲酸、乙酸、丙酸、丁酸、柠檬酸、苯甲酸,对甲基苯磺酸,对硝基苯甲酸,甲磺酸,三氟甲磺酸,三氟乙酸;所述路易斯酸包括但不限于三氟化硼,氯化锌,氯化镁,氯化铝,氯化锡,氯化铁;
缩合剂可以选自4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐、1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、0-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、0-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鑰六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷,可以是4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐或1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
方案3
本申请式(I-D)或式(II-D)所示的化合物的制备方法,其可以包含:
第一步:通式(P1)化合物和活化试剂在任选酸性或碱性条件下反应,得到通式(P2);
第二步:通式(P2)化合物和通式(Y1)化合物任选在酸性或碱性条件下反应,得到通式(P3);
第三步:通式(P3)化合物脱除保护基PG1得到通式(P4);
第四步:通式(P4)化合物和通式(Y2)化合物任选在酸性或碱性条件下反应,得到通式(P5);
第五步:通式(P4)化合物脱除保护基PG2,得到通式(P6);
第六步:通式(P6)化合物与通式(Y3)化合物任选在酸性或碱性条件下反应,得到式(I-D)所示的化合物;
其中,
AG为常用羟基、或氨基或其它基团的活化基团;
PG
1和PG
2为任意氨基、羧基或羟基的保护基;
SP
1、SP
2与SP
3可以共同组成本申请任一式(I-D)或式(II-D)所示的化合物所分别定义的Tr
I或Tr
II;L
1x、L
2、L
3可以分别如本申请任一式(I-D)所示的化合物中L
I-1x、L
I-2、L
I-
3所定义,或如本申请任一式(II-D)所示的化合物中L
II-1x、L
II-2、L
II-3所定义;SP
1、SP
2、SP
3也可以分别如本申请任一式(I-A)所示的化合物中SP
I-1、SP
I-2、SP
I-3所定义,或如本申请任一式(II-A)所示的化合物中SP
II-1、SP
II-2、SP
II-3所定义;
提供碱性条件的试剂包括有机碱和无机碱,所述的有机碱包括但不限于三乙胺,二乙胺,N-甲基吗啉,吡啶,六氢吡啶,NN-二异丙基乙胺,正丁基锂,二异丙基氨基锂,醋酸钾,叔丁醇钠,叔丁醇钾等;所述无机碱包括但不限于氢化钠,碳酸钾,碳酸钠,碳酸铯,氢氧化钠,氢氧化锂等;
提供酸性条件的试剂包括质子酸和路易斯酸,所述质子酸包括但不限于盐酸,硫酸,硝酸,亚硝酸,亚硫酸,磷酸,亚磷酸,甲酸、乙酸、丙酸、丁酸、柠檬酸、苯甲酸,对甲基苯磺酸,对硝基苯甲酸,甲磺酸,三氟甲磺酸,三氟乙酸;所述路易斯酸包括但不限于三氟化硼,氯化锌,氯化镁,氯化铝,氯化锡,氯化铁;
缩合剂可以选自4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐、1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、0-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、0-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鑰六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷,可以是4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉盐或1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
方案4
本申请式(I-C)或式(II-C)所示的化合物的制备方法,其可以包含:
配体Ab和本申请任一式(I-D)或式(II-D)所示的化合物在酸性、中性或碱性的缓冲液中反应可以得到式(I-C)或式(II-C)所示的化合物;
其中:Ab为含有至少1个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(I-C)或式(II-C)所示的化合物中的S原子与可以来源于Ab的巯基;
Tr、L
2、L
3可以分别如本申请任一式(I-D)所示的化合物中Tr
I、L
I-2、L
I-3所定义,或如本申请任一式(II-D)所示的化合物中Tr
II、L
II-2、L
II-3所定义;Ab、N
a可以分别如本申请任一式(I-C)所示的化合物中Ab
I、N
a-I所定义,或如本申请任一式(II-C)所示的化合物中Ab
II、N
a-II所定义;
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合。
方案5
本申请式(I-C)或式(II-C)所示的化合物的制备方法,其可以包含:
第一步,配体Ab和本申请任一式(I-D)或式(II-D)所示的化合物在酸性、中性或碱性的缓冲液中反应可以得到式(I-C)或式(II-C)所示的化合物;
其中:
其中:Ab为含有至少1个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(I-C)或式(II-C)所示的化合物中的S原子与可以来源于Ab的巯基;
第二步,本申请任一式(I-C)或式(II-C)所示的化合物在碱性的缓冲液中,与选定的温度下,孵育一定的时间,得到另一种本申请任一式(I-C)或式(II-C)所示的化合物;
Tr、L
2、L
3可以分别如本申请任一式(I-D)所示的化合物中Tr
I、L
I-2、L
I-3所定义,或如本申请任一式(II-D)所示的化合物中Tr
II、L
II-2、L
II-3所定义;Ab、N
a可以分别如本申请任一式(I-C)所示的化合物中Ab
I、N
a-I所定义,或如本申请任一式(II-C)所示的化合物中Ab
II、N
a-II所定义;
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸 缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合;选定的温度可以为5~60℃;孵育的时间可以为0~72小时。
方案6
本申请式(I-C)或式(II-C)所示的化合物的制备方法,其可以包含:
配体Ab和本申请任一式(I-D)或式(II-D)所示的具有能够与2个巯基偶联的基团的化合物在酸性、中性或碱性的缓冲液中反应得到式(I-C)或式(II-C)所示的化合物;
式(I-D)所示的具有能够与2个巯基偶联的基团的化合物可以包含选自以下组的L1
x基团:
其中每一个R
L1a,R
L1b和R
L1c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO
2、-CN、-OH、-SH、-NH
2、-C(O)H、-CO
2H、-C(O)C(O)H、-C(O)CH
2C(O)H、-S(O)H、-S(O)
2H、-C(O)NH
2、-SO
2NH
2、-OC(O)H、-N(H)SO
2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;
其中:Ab为含有至少2个自由巯基(-SH)的配体,其中自由巯基可由该配体经还原剂还原得到;还原剂包括但不限于三(2-羧乙基)膦,巯基乙醇,二硫苏糖醇,半胱氨酸,还原型谷胱甘肽等;特别地,可以还原配体链间的二硫键(-S-S-)以形成自由巯基;其中式(I-C)或式(II-C)所示的化合物中的S原子与可以来源于Ab的巯基;
Tr、L
1、L
1x、L
2、L
3可以分别如本申请任一式(I-D)所示的化合物中Tr
I、L
I-1、L
I-1x、L
I-2、L
I-3所定义,或如本申请任一式(II-D)所示的化合物中Tr
II、L
II-1、L
II-1x、L
II-2、L
II-3所 定义;Ab、N
a可以分别如本申请任一式(I-C)所示的化合物中Ab
I、N
a-I所定义,或如本申请任一式(II-C)所示的化合物中Ab
II、N
a-II所定义;
缓冲液选自pH 2到12的下列缓冲液,柠檬酸-柠檬酸钠缓冲液,磷酸-磷酸钠缓冲液,磷酸-磷酸钾缓冲液,磷酸二氢钠-磷酸氢二钠缓冲液,磷酸二氢钾-磷酸氢二钾缓冲液,琥珀酸-琥珀酸钠缓冲液,醋酸-醋酸钠缓冲液,硼酸-硼砂缓冲液,硼酸-硼酸钾缓冲液,硼砂-氢氧化钠缓冲液,组氨酸-盐酸缓冲液,甘氨酸-氢氧化钠缓冲液,精氨酸-盐酸缓冲液,碳酸氢钠-碳酸钠缓冲液,碳酸氢钾-碳酸钾缓冲液,Tris-盐酸缓冲液,氨水-氯化铵缓冲液,巴比妥钠-盐酸缓冲液,硼砂-碳酸钠缓冲液,硼酸-氯化钾缓冲液,或上述两种及两种以上缓冲液的组合。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的化合物、制备方法和用途等,而不用于限制本申请发明的范围。
实施例
实施例1
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Quan tum-I核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-D)、氘代氯仿(CDCl
3)、氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS),化学位移是以10_6(ppm)作为单位给出。
MS的测定用Angilent 6230 ESI-TOF质谱仪(生产商:安捷伦,c型号:6230)
UPLC的测定用Waters AcquityUPLCSQD液质联用仪(Poroshell 120 EC-C18,2.1mm x 50mm,1.9微米色谱柱)。
HPLC的测定使用安捷伦1260高压液相色谱仪(TOSOH G3000 SW SEC色谱柱)。
UV的测定使用Thermonanodrop2000紫外分光光度计。
酶联免疫测定用EnVision酶标仪(PerkinElmer公司)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm0.2mm,薄层层析分离纯化产品采用的规格是0.4mm0.5mm娃胶板。
柱层析一般使用烟台黄海200~300目硅胶为载体。
本申请的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCRGmbH&Co.KG,AcrosOrgannics,AldrichChemicalCompany,韶远化学科技(AccelaChemBioInc)、达瑞化学品等公司。
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
实施例中如无特殊说明,反应中的溶液是指水溶液。
实施例中如无特殊说明,反应的温度为室温。室温为最适宜的反应温度,温度范围是20℃~30℃。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括:A:二氯甲烷和异丙醇体系,B:二氯甲烷和甲醇体系,C:石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
本申请部分化合物是通过TOF-LC/MS来表征的。TOF-LC/MS使用安捷伦6230飞行时间质谱仪和安捷伦1290-Infinity超高效液相色谱仪。
制备例1.1
步骤1.(S)-(2-((((((9H-芴-9-基)甲氧基)羰基)氨基)丙酰胺基)乙酸甲酯的合成
向((((9H-芴-9-基)甲氧基)羰基)-L-丙氨酰甘氨酸(69.0g,195mmol)的THF(1.5L)溶液中加入500毫升甲苯,再加入吡啶(18g,234mmol)和四乙酸铅(109g,235mmol),加完后,混合溶液80度反应5h,TLC(DCM/MeOH=10/1)显示反应完毕,将反应液冷至室温,用硅藻土过滤出去不容物,在减压浓缩,将得到的残留物溶于EA(1L),用饱和NaCl(500mL)洗后,用无水硫酸钠干燥有机相,旋干后柱层析(PE:EA=10:1至PE:EA=2:1)得到白色粉末40g,收率为53%。
步骤2.(9H-芴-9-基)甲基((S)-1-((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-1-氧丙烷-2-基)氨基甲酸酯的合成
将(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-4H-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-4-酮和(S)-(2-((((((9H-芴-9-基)甲氧基)羰基)氨基)丙酰胺基)乙酸甲酯(552mg,1.44mmol)溶于无水四氢呋喃(10mL)中,氮气置换三次后,冷却至-65度,加入叔丁醇锂溶液(0.07),并在-65度搅拌30分钟。TLC监测原料消失。反应液加入饱和碳酸氢钠(10mL)淬灭反应,用乙酸乙酯(4*3mL)萃取,有机相用无水硫酸钠干燥后,浓缩,粗品用反相柱纯化(用MeCN:H2O=4:1),得到190mg白色固体,收率:31.8%。
步骤3.(S)-2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧杂-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二恶唑-8b-基)-2-氧乙氧基)甲基)丙酰胺的合成
氮气保护下,在0℃下,向(9H-芴-9-基)甲基((S)-1-((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-1-氧丙烷-2-基)氨基甲酸酯(280mg,不纯)的DCM(5.6ml)反应中滴加哌啶(2.8mL),并在0℃下搅拌1.5h。LC-MS显示原料反应完全。将反应液滴加到50ml甲叔醚中,析出白色固体,过滤,并用甲叔醚(50mL)洗两遍后,将固体用油泵拉干后得200mg灰色固体,收率不计(粗品)。
步骤4.(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰基)-L-丙氨酸的合成
将2,5-二氧吡咯烷-1-基6-(2,5-二氧-2-,5-二氢-1H-吡咯-1-基)己酸酯(6g,19.5mmol)和L-丙氨酸(2.6g,29.25mmol)溶于DCM中,加入DIPEA(39mmol,5.04g)和DMAP,混合物25度反应16h。TLC(PE/EA=1/1)显示反应完全。旋干溶剂,加入1N盐酸(150ml),EA(15ml)淬取三次,无水硫酸钠干燥,有机相旋干,用MTBE(200ml)打浆16h,过滤得到无色粉末4.55g,产率为83%。
步骤5.N-((S)-1-(((S)-1-(((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-8b-基)-2-氧代乙氧基)甲基)氨基)-1-氧代丙烷-2-基)氨基)-1-氧代丙烷-2-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺的合成
将(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰基)-L-丙氨酸与(S)-2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二恶唑-8b-基)-2-氧乙氧基)甲基)丙酰胺的粗产品(200mg)溶于无水DMF中,加入HATU(184mg,0.484mmol)的DMF(2ml)溶液并在0℃下搅拌2小时,LCMS显示原料反应完全。将反应液滴加到PH=4的柠檬酸水溶液(100ml)中,析出固体,滤干,经prep-HPLC(0.1%TFA)制备冻干后得黄色固体14mg,收率:4.8%。LC-MS:[M+H]835.44。
制备例1.2
步骤1乙酸2-((((((9H-芴-9-基)甲氧基)羰基)氨基)乙酰氨基)乙酸甲酯的合成
向((((9H-芴-9-基)甲氧基)羰基)甘氨酰甘氨酸(40g,113mmol)的1.5L THF溶液中加入500毫升甲苯,再加入吡啶(10.4g,136mmol)和四乙酸铅(63g,136mmol),混合溶液80度反应5h,TLC(DCM/MeOH=10/1)显示反应完毕,将反应液冷至室温,用硅藻土过滤出去不容物,再减压浓缩,将得到的残留物溶于EA(1L),用饱和NaCl(500mL)洗后,用无水硫酸钠干燥有机相,旋干柱层析(PE:EA=10:1至PE:EA=2:1)得到白色粉末29.5g,收率为71%。
步骤2(9H-芴-9-基)甲基(2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧代乙氧基)甲基)氨基)-2-氧代乙基)氨基甲酸酯的合成
将乙酸2-((((((9H-芴-9-基)甲氧基)羰基)氨基)乙酰氨基)乙酸甲酯(4.3mmol,1.58g)与(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-4H-萘[2,1:4,5]茚并[1,2-d][1,3]二氧代-4-酮(400mg,0.86mmol)溶于无水四氢呋喃(10mL)中,氮气置换三次后,冷却至-65度,加入叔丁醇锂溶液(0.07eq),并在-65度搅拌30分钟。TLC监测原料消失。反应液加入饱和碳酸氢钠(10mL)淬灭反应,用乙酸乙酯(4*3mL)萃取,有机相用无水硫酸钠干燥后,浓缩,粗品用反相柱纯化(用MeCN:H2O=4:1),得到292mg白色固体,收率:44%。
步骤3 2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺的合成
氮气保护下,在0℃下,向(9H-芴-9-基)甲基(2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧代乙氧基)甲基)氨基)-2-氧代乙基)氨基甲酸酯(280mg,0.36mmol)的DCM(5.6ml)反应中滴加乙二胺(1mL),并在0℃下搅拌1.5h。LC-MS显示原料反应完全。将反应液滴加到50ml甲叔醚中,析出白色固体,过滤,并用甲叔醚(50mL)洗两遍后,将固体用油泵拉干后得244mg灰色固体,收率不计(不纯)。
步骤4(((9H-芴-9-基)甲氧基)羰基)叔丁基甘氨酰-L-苯丙氨酸酯的合成
干燥三口瓶中加入((((9H-芴-9-基)甲氧基)羰基)甘氨酰甘氨酸(10.4g,29.3mmol),L-苯丙氨酸叔丁酯(7.56g,29.3mmol),HATU(13.3g,35.2mmol)和DIEA(9.10g,70.0mmol),混合物在室温反应16h,TLC(PE/EA=1/1)显示反应完全。加入水(20ml),EA(20ml)淬取三次,有机相饱和氯化钠(30ml)洗,无水硫酸钠干燥,过滤,有机相旋干柱层析(DCM:MeOH=100:1至25:1)得到14.1g淡黄色固体,收率为86%。
步骤5((((9H-芴-9-基)甲氧基)羰基)甘氨酰甘氨酰-L-苯丙氨酸的合成
在氩气保护下,向(((9H-芴-9-基)甲氧基)羰基)叔丁基甘氨酰-L-苯丙氨酸酯(6g,10.7mmol)的DCM(140ml)溶液中加入TFA(15ml),并在25度下反应16h,LCMS显示反应完毕,直接旋干有机相,MTBE(30ml)打浆16h,过滤得到白色粉末5g,产率为92%。
步骤6甘氨酰甘氨酰-L-苯丙氨酸的合成
氩气保护下,向((((9H-芴-9-基)甲氧基)羰基)甘氨酰甘氨酰-L-苯丙氨酸(3.5g,7.0mmol)的DCM(50mL)溶液中加入乙二胺10ml,混合物25搅拌5h;TLC(DCM/MeOH=10/1)显示反应完毕,原料消失;将反应完旋干,甲基叔丁基醚(10ml)打浆三次,静置后倒出澄清液得不溶物,不溶物油泵拉干得到3.3g粗品。
步骤7(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰)甘氨酰甘氨酰-L-苯丙氨酸的合成
甘氨酰甘氨酰-L-苯丙氨酸粗品(3g,10.7mmol)溶于50ml二氯甲烷中,加入2,5-二氧吡咯烷-1-基6-(2,5-二氧-2-,5-二氢-1H-吡咯-1-基)己酸酯(16.1mmol,4.93g)及DIEA,混合物25度反应16h。TLC(PE/EA=1/1)显示反应完全。旋干溶剂,加1N的盐酸(50ml),EA(50ml)淬取三次,无水硫酸钠干燥,有机相旋干,用MTBE(20ml)打浆,过滤得到白色粉末2.62g,产率为52%。
步骤8N-((S)-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-yl)-1,6,9,12,15-五氧-3--3-氧杂-5,8,11,14-四氮杂十六烷-16-基)-6-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)己酰胺的合成
氩气保护下,将2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺(150mg,0.27mmol)溶于无水DMF,加入(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰)甘氨酰甘氨酰-L-苯丙 氨酸(0.41mmol,193mg),HATU,DIEA及DMAP,在25℃下反应1小时,LCMS显示原料反应完全。将反应液滴加到pH=4的柠檬酸水溶液(15ml)中,析出黄色固体,滤干,经prep-HPLC(0.1%TFA)制备冻干后得黄色固体17mg,收率:6.3%。LC-MS:[M+H]=1011.11。
制备例1.3
步骤1 5-烯丙基-1-苄基((((9H-芴-9-基)甲氧基)羰基)甘氨酸-L-谷氨酸的合成
将5-烯丙基1-苄基L-谷氨酸(4g,14.4mmol)溶于干燥的二氯甲烷中,加入((((9H-芴 -9-基)甲氧基)羰基)甘氨酸(4.3g,14.4mmol),冷至0℃,加入EDCI(21.6mmol,4.14g)、DIEA(21.6mmol,2.79g)及DMAP(2.16mmol,263mg),于0℃下反应2小时,TLC监测。反应完全后,加入1N的盐酸中和反应,DCM萃取,并将萃取液用1N盐酸洗涤2遍,饱和碳酸氢钠洗涤1遍,干燥浓缩。粗产品用PE/EA=20:1过柱得到白色固体6.97g,收率87%。
步骤2(S)-5-(烯丙氧基)-2-(2-氨基乙酰氨基)-5-氧戊酸的合成
5-烯丙基-1-苄基((((9H-芴-9-基)甲氧基)羰基)甘氨酸-L-谷氨酸(5g,8.98mmol)溶于100ml甲醇中,加入2ml甲酸,加入0.5g 10%Pd/C,于氢气气氛下氢化48小时。LC-MS显示原料完全转化为目标产物后,过滤Pd/C,旋干溶剂,并用MTBE反复旋干,将甲酸尽可能地除去,得到白色固体1.86g,收率85%。
步骤3(S)-5-(烯丙氧基)-2-(2-(3-(3,2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)乙酰氨基)-5-氧戊酸的合成
(S)-5-(烯丙氧基)-2-(2-氨基乙酰氨基)-5-氧戊酸(1.2g,4.91mmol)溶于25ml干燥的二氯甲烷,冷却至0℃,加入2,5-二氧环戊基3-(2,5-二氧-2-,5-二氢-1H-吡咯-1-基)丙酸酯(7.36mmol,1.95g)、DIEA(14.73mmol,1.9g)及DMAP(1.47mmol,179mg),于0℃下反应4小时,反应结束后,加入柠檬酸水溶液,用DCM稀释,用柠檬酸水溶液洗涤三次,干燥浓缩。粗品经DCM/MeOH=15:1过柱,得到白色固体1.3g,收率67%。
步骤4(9H-芴-9-基)甲基(2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧代乙氧基)甲基)氨基)-2-氧代乙基)氨基甲酸酯的合成
将乙酸2-((((((9H-芴-9-基)甲氧基)羰基)氨基)乙酰氨基)乙酸甲酯(4.3mmol,1.58g)与(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-4H-萘[2,1:4,5]茚并[1,2-d][1,3]二氧代-4-酮(400mg,0.86mmol)溶于无水四氢呋喃(10mL)中,氮气置换三次后,冷却至-65度,加入叔丁醇锂溶液(0.07eq),并在-65度搅拌30分钟。TLC监测原料消失。反应液加入饱和碳酸氢钠(10mL)淬灭反应,用乙酸乙酯(4*3mL)萃取,有机相用无水硫酸钠干燥后,浓缩,粗品用反相柱纯化(用MeCN:H2O=4:1),得到292mg白色固体,收率:44%。
步骤5 2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环 己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺的合成
氮气保护下,在0℃下,向(9H-芴-9-基)甲基(2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧代乙氧基)甲基)氨基)-2-氧代乙基)氨基甲酸酯(280mg,0.36mmol)的DCM(5.6ml)反应中滴加乙二胺(1mL),并在0℃下搅拌1.5h。LC-MS显示原料反应完全。将反应液滴加到50ml甲叔醚中,析出白色固体,过滤,并用甲叔醚(50mL)洗两遍后,将固体用油泵拉干后得244mg灰色固体,收率不计(不纯)。
步骤6烯丙基(S)-5-((2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS))-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)氨基)-4-(2-(3-(2,5-二氧杂-2,5-二氢-1H-吡咯-1-基)丙酰胺基)乙酰氨基)-5-氧戊酸的合成
(S)-5-(烯丙氧基)-2-(2-(3-(3,2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)乙酰氨基)-5-氧戊酸(0.72mmol,284mg)溶于干燥的二氯甲烷,冷却至0℃,并于氮气保护下分别加入HATU,2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺(0.36mmol)、DIEA及DMAP,在0℃下反应4小时,LC-MS监测,待原料消失后,加入1N盐酸中和反应体系,并用DCM萃取,干燥浓缩。粗品经制备液相得到白色固体86.9mg,收率26%。
步骤7(S)-5-((2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)氨基)-4-(2-(3-(2,5-二氧代-2,5-二氢)-1H-吡咯-1-基)丙酰胺基)乙酰胺基)-5-氧戊酸的合成
烯丙基(S)-5-((2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS))-10-环己基-7-羟基-6a,8a-二甲基-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)氨基)-4-(2-(3-(2,5-二氧杂-2,5-二氢-1H-吡咯-1-基)丙酰胺基)乙酰氨基)-5-氧戊酸(223mg, 0.24mmol)溶于5ml干燥的二氯甲烷,在氩气保护下加入四三苯基膦钯(0.024mmol,27mg),于25℃下反应2小时,LC-MS监测,待原料消失后,加入柠檬酸水溶液,DCM萃取,干燥浓缩。经制备HPLC得到白色固体80.9mg,收率38%。LC-MS:[M+H]=894.41。
制备例1.4
步骤1 1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3-氧代-7,10,13,16-四氧代-4-氮杂十二烷-19-油酸的合成
1-氨基-3,6,9,12-四氧杂十五烷-15-油酸(3g,11.3mmol)溶于100ml干燥的DCM,加入2,5-二氧环戊基3-(2,5-二氧-2-,5-二氢-1H-吡咯-1-基)丙酸酯(13.6mmol,3.6g),DIEA(16.9mmol,2.19g),于25℃下反应18小时,TLC监测,原料消失后,加入柠檬酸水溶液, 二氯甲烷萃取,干燥浓缩。用DCM-MeOH=30:1过柱,得到无色油状液体3.72g,收率79%。
步骤2 2,5-二氧环戊基1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3-氧代-7,10,13,16-四氧环-4-氮杂壬烷-19-酸酯的合成
1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3-氧代-7,10,13,16-四氧代-4-氮杂十二烷-19-油酸(2.6g,6.24mmol)溶于40ml干燥的二氯甲烷,冷却至0℃,在氮气保护下加入羟基丁二酰亚胺(11.2mmol,1.29g),DIEA(12.48mmol,1.61g)及DMAP(1.25mmol,152mg),于25℃下反应4小时,LC-MS监测,原料消失后,加入柠檬酸水溶液,用DCM萃取,无水硫酸钠干燥后浓缩。用DCM-MeOH=40:1过柱得到无色油状液体2g,收率63%。
步骤3(1-(2,5-二氧-2-2,5-二氢-1H-吡咯-1-基)-3-氧-7,10,13,16-四氧-4--4-氮杂十二烷-19-基)甘氨酰甘氨酰-L-苯丙氨酸的合成
2,5-二氧环戊基1-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-3-氧代-7,10,13,16-四氧环-4-氮杂壬烷-19-酸酯(1.35g,2.64mmol)和甘氨酰甘氨酰-L-苯丙氨酸(3.96mmol,1.1g)溶于15ml干燥的二氯甲烷中,加入DIEA(5.28mmol,682mg)及DMAP(0.53mmol,65mg),0℃下反应4小时,TLC点板显示反应完全,加入柠檬酸水溶液,用DCM萃取,用柠檬酸水溶液洗涤三次,干燥浓缩,粗品用DCM-MeOH=10:1过柱得到白色易吸潮固体983mg,收率55%。
步骤4N-((S)-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二恶唑-8b-基)-1,6,9,12,15-五恶唑-3-氧杂-5,8,11,14-四氮杂十六烷-16-基)-1-(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺)-3,6,9,12-四氧杂十五烷-15-酰胺的合成
(1-(2,5-二氧-2-2,5-二氢-1H-吡咯-1-基)-3-氧-7,10,13,16-四氧-4--4-氮杂十二烷-19-oyl)甘氨酰甘氨酰-L-苯丙氨酸(257mg,0.38mmol)溶于干燥的DMF中,依次加入HATU(0.57mmol,216mg),2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2,1:4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺(0.38mmol,209mg)和DIEA(0.57mmol,74mg),于0℃下反应4小时,LC-MS监测反应,原料消失后,加入柠檬酸水溶液,DCM/MeOH=10:1萃取,干燥浓缩,经制备HPLC得到白色易吸潮固体50.6mg,收率11%。LC-MS:[M+H]=1216.60。
制备例1.6
步骤1苄基(S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧代- 2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-48-酸酯的合成
2,5,8,11,14,17,20,23,26,29,32,35,38-三氮杂苯并四氢呋喃-41-油酸(5g,7.9mmol)溶于100ml干燥的二氯甲烷中,依次加入苄基(((9H-芴-9-基)甲氧基)羰基)-L-赖氨酸(11.85mmol,5.43g),EDCI(2.27g,11.9mmol),冷却至0℃,加入DIEA(23.7mmol,3.06g)和DMAP(2.37mmol,289mg),自然升至室温,搅拌4小时。TLC监测反应,原料消失后,加入1N盐酸猝灭反应,DCM萃取,干燥浓缩。粗产品经DCM/MeOH=50:1过柱得到无色油状液体6.1g,收率72%。
步骤2(S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-48-酸酯的合成
苄基(S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-48-酸酯(4.2g,3.91mmol)溶于40ml甲醇中,加入0.3g 10%Pd/C,于室温下,在氢气气氛中氢化过夜。TLC监测原料消失后,过滤掉Pd/C,在旋蒸上旋干得到无色油状液体粗品3.75g,不经纯化直接进行下一步反应。
步骤3苄基((S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-48-酰基)甘氨酰甘氨酰-L-苯丙氨酸的合成
(S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-48-酸酯粗品(1.7g,1.73mmol)溶于30ml干燥的二氯甲烷中,加入苄基缩水甘油基-L-苯丙氨酸(2.6mmol,957mg),冷却至0℃,依次加入HATU(2.6mmol,987mg)和DIEA(2.6mmol,335mg),于0℃反应4小时,LC-MS显示原料消失后,加入柠檬酸水溶液,DCM萃取,干燥浓缩。粗品经DCM/MeOH=100:1过柱得到无色油状液体1.57g,收率0.68。
步骤4((S)-47-(((((9H-fluoren-9-yl)methoxy)羰基)氨基)-41-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-四氢呋喃-48-酰基)甘氨酰甘氨酰-L-苯丙氨酸的合成
苄基((S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-48-酰基)甘氨酰甘氨酰-L-苯丙氨酸(1.5g,1.12mmol)溶于20ml无水甲醇中,加入0.1g 10%Pd/C,于室温下在氢气气氛中氢化过夜。TLC显示原料消失后,过滤浓缩,得到白色易吸潮固体1.27g,收率0.91%,不经纯化直接进行下一步。
步骤5(9H-芴-9-基)甲基((47S,56S)-56-苄基-65-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-8b-基)-41,48,51,54,57,60,65-七氧代-2,5,8,11,14,17,20,23,26,29,32,35,38,63-十四烷-42,49,52,55,58,61-六氮杂六十碳烷-47-基)氨基甲酸酯的合成
((S)-47-(((((9H-芴-9-基)甲氧基)羰基)氨基)-41-氧杂-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂-42-氮杂辛烷-四氢呋喃-48-酰基)甘氨酰甘氨酰-L-苯丙氨酸(1.1g,0.88mmol)溶于干燥的DMF中,加入2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺(1.3mmol,727mg),HATU(1.3mmol,504mg)及DIEA(1.3mmol,171mg),于0℃下反应6小时,LC-MS显示原料消失后,加入柠檬酸水溶液,DCM萃取,干燥浓缩,经DCM/MeOH=10:1过柱,得到白色易吸潮固体594mg,收率38%。
步骤6N-((10S,19S)-19-氨基-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-8b-基)-1,6,9,12,15,18-六氧代-3-氧杂-5,8,11,14,17-五氮杂二十三碳烷-23-基)-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂四十碳烷-41-酰胺的合成
(9H-芴-9-基)甲基((47S,56S)-56-苄基-65-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-8b-基)-41,48,51,54,57,60,65-七氧代-2,5,8,11,14,17,20,23,26,29,32,35,38,63-十四烷-42,49,52,55,58,61-六氮杂六十碳烷-47-基)氨基甲酸酯(550mg,0.31mmol)溶于10ml DCM,冷却至0℃,逐滴加入1ml甲胺乙醇溶液,于0℃下搅拌6小时,LC-MS显示原料消失后,加入石油醚充分搅拌,旋干溶剂,并用MTBE反复旋干,得到微黄色胶状液体480mg,不经纯化直接进行下一步反应。
步骤7N-(((10S,19S)-10-苄基-1-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-8b-基)-19-(((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)氨基)-1,6,9,12,15,18-六氧代-3-氧杂-5,8,11,14,17-五氮杂十三碳烷-23-基)- 2,5,8,11,14,17,20,23,26,29,32,35,38-三氮杂苯并四氢呋喃-41-酰胺的合成
N-((10S,19S)-19-氨基-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧代-8b-基)-1,6,9,12,15,18-六氧代-3-氮杂-5,8,11,14,17-五氮杂十三碳烷-23-基)-2,5,8,11,14,17,20,23,26,29,32,35,38-十三氧杂十四碳烷-41-酰胺(0.31mmol)溶于干燥的DMF中,加入2,5-二氧环戊基3-(2,5-二氧-2-,5-二氢-1H-吡咯-1-基)丙酸酯(0.62mmol,164mg)和DIEA(0.62mmol,80mg),于0℃下反应6小时,LC-MS监测。LC-MS显示原料消失后,加入柠檬酸水溶液,用DCM/MeOH=10:1萃取,干燥浓缩。经制备HPLC得到白色易吸潮固体135mg,收率26%。LC-MS:[M+H]=1683.88。
制备例1.7
步骤1(9H-芴-9-基)甲基((S)-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-1,6,9,12,15-五氧杂-3-氧杂-5,8,11,14-四氮杂十六烷-16-基)氨基甲酸酯
((((9H-芴-9-基)甲氧基)羰基)甘氨酰甘氨酰-L-苯丙氨酸(0.74mmol,372mg)干燥的DCM中,加入2-氨基-N-((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)乙酰胺(340mg,0.62mmol),冷却至0℃,依次加入HATU(282mg)和DIEA(96mg),于0℃下搅拌4小时。LC-MS显示原料消失后,加入碳酸氢钠水溶液,DCM萃取,干燥浓缩。DCM/MeOH=20:1过柱得到灰白色固体288mg,收率45%。
步骤2(S)-2-(2-(2-氨基乙酰氨基)乙酰氨基)-N-(2-(((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二烷基-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)-3-苯基丙酰胺的合成
(9H-芴-9-基)甲基((S)-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-1,6,9,12,15-五氧杂-3-氧杂-5,8,11,14-四氮杂十六烷-16-基)氨基甲酸酯(280mg,0.27mmol)溶于5ml干燥的DCM中,冷却至0℃,逐滴加入0.5ml甲胺乙醇溶液,于0℃下搅拌6小时,LC-MS显示原料消失后,加入石油醚充分搅拌,旋干溶剂,并用MTBE反复旋干,得到微黄色胶状液体,不经纯化直接进行下一步反应。
步骤3(S)-2-(2-(2-(2-(3-(2-溴乙酰氨基)丙酰胺基)乙酰氨基)乙酰氨基)-N-(2-(((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]二恶醇-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)-3-苯基丙酰胺的合成
(S)-2-(2-(2-氨基乙酰氨基)乙酰氨基)-N-(2-(((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二烷基-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基) 氨基)-2-氧乙基)-3-苯基丙酰胺(0.27mmol)溶于干燥的DMF中,依次加入全氟苯基3-(2-溴乙酰氨基)丙酸酯(0.54mmol,203mg)和DIEA(0.54mmol,70mg),于0℃下反应4小时,LC-MS监测。原料消失后,加入柠檬酸水溶液,DCM/MeOH=10:1萃取,干燥浓缩。经制备HPLC得到白色固体38mg,收率14%。LC-MS:[M+H]=1009.31。
制备例1.8
步骤1 3-(3,4-二溴-2,5-二氧-2,5-二氢-1H-吡咯-1-基)丙酸的合成
3,4-二溴呋喃-2,5-二酮(25.6g,100mmol)和3-氨基丙酸(13.1g,100mmol)加入到500ml甲苯中,加入20ml AcOH,加热到120℃搅拌3小时。之后,反应混合物冷却到室温,旋干 溶剂,并用MTBE反复旋干,将AcOH带走,所得粗品用石油醚/乙酸乙酯=1:1过柱得到白色固体24.2g,收率74%。
步骤2(S)-2-(2-(2-氨基乙酰氨基)乙酰氨基)-N-(2-(((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二烷基-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)-3-苯基丙酰胺的合成
(9H-芴-9-基)甲基((S)-10-苄基-1-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-1,6,9,12,15-五氧杂-3-氧杂-5,8,11,14-四氮杂十六烷-16-基)氨基甲酸酯(120mg,0.12mmol)溶于5ml干燥的DCM中,冷却至0℃,搅拌下加入0.5ml甲胺乙醇溶液,0℃下反应2小时,TLC监测显示原料消失后,在旋蒸上旋干,并用MTBE反复旋干多次,得到黄色固体,不经纯化直接投入下一步。
步骤3(S)-N-(2-((((2-(((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氢-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)-2-(2-(2-(3-(3,4-二溴-2,5-二氧杂)-2,5-二氢-1H-吡咯-1-基)丙酰胺基)乙酰胺基)乙酰胺基)-3-苯基丙酰胺的合成
3-(3,4-二溴-2,5-二氧-2,5-二氢-1H-吡咯-1-基)丙酸(0.24mmol,92mg)和(S)-2-(2-(2-氨基乙酰氨基)乙酰氨基)-N-(2-(((((2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-环己基-7-羟基-6a,8a-二甲基-4-氧代1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二烷基-8bH-萘[2',1':4,5]茚并[1,2-d][1,3]二氧杂-8b-基)-2-氧乙氧基)甲基)氨基)-2-氧乙基)-3-苯基丙酰胺(0.12mmol)溶于干燥的DMF中,冷却至0℃,在氮气保护下加入HATU和DIEA,在0℃下搅拌6小时,LC-MS显示原料消失后,加入柠檬酸水溶液,用DCM/MeOH=10:1萃取,干燥浓缩,经制备HPLC得到黄色固体50mg,收率35%。LC-MS:[M+H]=1124.33
制备例1.9
ADC制备
在37℃条件下,向抗体Adalimumab(Humira,其轻链可包含SEQ ID NO:18所示的氨基酸序列,且其重链可包含SEQ ID NO:20所示的氨基酸序列)的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物L-5(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25°0振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液,含0.001M的EDTA),得到式(I-C)的示例性产物的PBS缓冲液(5.0mg/mL,1.1mL),于4℃冷冻储存。N
a-I可以经LC-MS检测。
制备例1.10
ADC制备
在37℃条件下,向抗体Adalimumab(Humira,其轻链可包含SEQ ID NO:18所示的氨基酸序列,且其重链可包含SEQ ID NO:20所示的氨基酸序列)的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基) 膦的水溶液(10mM,0.054mL,0.54nmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物L-5(1.67mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25°0振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液,含0.001M的EDTA),得到式(I-C)的示例性产物的PBS缓冲液(5.0mg/mL,1.1mL)。
将ADC的PBS缓冲液的pH值用1M的Tris缓冲液调节至pH=9,置于37℃下孵育24小时,用1mol/L的柠檬酸缓冲液调节pH直6.5,得到ADC-170(3.3mg/mL,5.5ml)。N
a-I可以经LC-MS检测。
制备例1.11
在37℃条件下,向抗体Adalimumab(Humira,其轻链可包含SEQ ID NO:18所示的氨基酸序列,且其重链可包含SEQ ID NO:20所示的氨基酸序列)的PB缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;2.5ml,9.96mg/ml,0.168nmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.134mL,1.34nmol),置于水浴振荡器,于37℃振荡反应3小时, 停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/ml,并取出2.0ml溶液往下反应。
将化合物L-74(2.38mg,2.02nmol)溶解于0.10mL DMA中,加入到上述2.0ml溶液中,置于水浴振荡器,于25°0振荡反应3小时,停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液,含0.001M的EDTA),得到式(I-C)的示例性产物ADC-74的PBS缓冲液(5.0mg/mL,1.1mL)。N
a-I可以经LC-MS检测。
制备例1.12
步骤1将化合物10A(5g,12.68mmol)、10B(2.57g,16mmol),NaHCO
3(1.43g,17mmol)溶于DME(50mL),H
2O(20mL)中,氮气保护并在室温搅拌17小时。LCMS监测反应结束。将反应液浓缩,再倒入100mL水中,EA(100mL)萃取,用5%HCl调pH至2-3,分液并用饱和NaCl洗涤,无水Na
2SO
4干燥,旋干浓缩得5.5g白色固体10C,收率:98%。MS-ESI:m/z 441.0[M+H]
+。
步骤2将化合物10D(3.2g,5.93mmol)溶于DCM(12mL)及MeOH(12mL)中加入至50mL三口瓶,滴加2%NaOH的MeOH溶液(5.5mL),室温下反应2小时。TLC(PE/EA=2/1)检测原料反应完全。将反应液加入水(50mL)中,用DCM(50mL)萃取分液,用饱和NaCl洗涤,无水Na
2SO
4干燥。浓缩后过柱(PE:EA=2:1),得2.4g白色晶体10E,收率:90%。MS-ESI:m/z 471.3[M+H]
+。
步骤3将化合物10F(6.3g,17mmol)、10E(4g,8.5mmol)溶于THF(40mL)中, 氮气保护并降温至5℃,滴加t-BuOLi(2.2M/THF)(12.7mL,12.7mmol)的THF(2mL)溶液,加完后5℃反应2小时。将反应液倒入200mL水中,EA(200mL)萃取,分液并用饱和NaCl洗涤,无水Na
2SO
4干燥。浓缩后过柱(PE/EA=1/1),得3.7g白色固体10G,收率:55.9%。MS-ESI:m/z 779.4[M+H]
+。
步骤4向化合物10G(3.5g)的DCM(48mL)中加入DEA(16mL),在0℃反应2小时。TLC显示反应完全。将反应液浓缩,并用DCM(50mL*3)溶解旋干后,过反相得800mg白色固体10H,收率:30%。MS-ESI:m/z 557.3[M+H]
+。
步骤5在氮气保护下,0℃下向化合物10H(650mg,1.17mmol),10C(514mg,1.17mmol),DMF(13mL)和DIEA(377mg,2.9mmol),再滴加HATU(533mg,1.4mmol)的DMF(3mL)溶液,加完后在0℃反应2小时。LCMS显示反应结束。将反应液浓缩后过正相纯化得660mg白色固体10I,收率:55%。MS-ESI:m/z 979.1[M+H]
+。
步骤6氮气保护下,在0℃下,向化合物10I(300mg,0.306mmol)的THF(6mL)溶液中滴加5%LiOH水溶液(2mL),并在0-5℃反应2小时。LCMS显示反应完全。将反应液用PE(30mL),H
2O(30mL)萃取两次后,水相用Na
2HPO
4和NaH
2PO
4缓冲溶液
(pH=4)调节pH至6-7,水相冻干,直接过反向柱(乙腈:水=40%:60%),得112mg白色粉末10J,收率:29.5%。MS-ESI:m/z 743.9[M+H]
+。
步骤7在氮气保护下,向化合物10J(65mg,0.087mmol),TEA(88.5mg,0.87mmol)的THF(3mL)及H
2O(0.5mL)溶液中加入溴乙酰溴(70mg,0.35mmol),并在0℃下反应10min。LCMS显示原料反应完全。将反应液直接送制备纯化得21mg白色固体10,收率:27.7%。MS-ESI:m/z 863.3[M+H]
+。
1H NMR(400MHz,DMSO)δ8.80-8.70(m,1H),8.60-8.50(m,1H),8.32(d,J=7.8Hz,1H),8.20-8.10(m,1H),7.34(d,J=10.1Hz,1H),6.19(d,J=10.1Hz,1H),5.94(s,1H),4.90-4.70(m,2H),4.60(d,J=6.7Hz,2H),4.44(d,J=18.9Hz,1H),4.38–4.30(m,2H),4.32-4.20(m,2H),3.95(s,2H),3.90–3.80(m,2H),3.75-3.65(m,2H),2.40-2.15(m,4H),2.15-2.00(m,3H),1.90-1.75(m,3H),1.75-1.50(m,9H),1.40(s,3H),1.21–0.90(m,7H),0.82(s,3H).
制备例1.13
步骤1向化合物11A(40g,113mmol)的1.5L THF溶液中加入500毫升甲苯,再加入吡啶(10.4g,136mmol)和四乙酸铅(63g,136mmol),混合溶液80度反应5h,TLC(DCM/MeOH=10/1)显示反应完毕,将反应液冷至室温,用硅藻土过滤出去不容物,再减压浓缩,将得到的残留物溶于EA(1L),用饱和NaCl(500mL)洗后,用无水硫酸钠干燥有机相,旋干柱层析(PE:EA=10:1至PE:EA=2:1)得到29.5g白色粉末11B,收率为71%。
步骤2将化合物11B(4.3mmol,1.58g)与化合物11C(400mg,0.86mmol)溶于无水四氢呋喃(10mL)中,氮气置换三次后,冷却至-65度,加入叔丁醇锂溶液(0.07eq),并在-65度搅拌30分钟。TLC监测原料消失。反应液加入饱和碳酸氢钠(10mL)淬灭反应,用乙酸乙酯(4*3mL)萃取,有机相用无水硫酸钠干燥后,浓缩,粗品用反相柱纯化(用MeCN:H2O=4:1),得到292mg白色固体11D,收率:44%。
步骤3氮气保护下,在0℃下,向化合物11D(280mg,0.36mmol)的DCM(5.6ml)反应中滴加乙二胺(1mL),并在0℃下搅拌1.5h。LC-MS显示原料反应完全。将反应液滴加到50ml甲叔醚中,析出白色固体,过滤,并用甲叔醚(50mL)洗两遍后,将固体用油泵拉干后得244mg灰色固体11E,收率不计(不纯)。
步骤4干燥三口瓶中加入11F(10.4g,29.3mmol),L-苯丙氨酸叔丁酯11G(7.56g,29.3mmol),HATU(13.3g,35.2mmol)和DIEA(9.10g,70.0mmol),混合物在室温反应16h,TLC(PE/EA=1/1)显示反应完全。加入水(20ml),EA(20ml)淬取三次,有机相饱和氯化钠(30ml)洗,无水硫酸钠干燥,过滤,有机相旋干柱层析(DCM:MeOH=100:1至25:1)得到14.1g淡黄色固体11H,收率为86%。
步骤5在氩气保护下,向化合物11H(6g,10.7mmol)的DCM(140ml)溶液中加入TFA(15ml),并在25度下反应16h,LCMS显示反应完毕,直接旋干有机相,MTBE(30ml)打浆16h,过滤得到5g白色粉末11I,产率为92%。
步骤6氩气保护下,向化合物11I(3.5g,7.0mmol)的DCM(50mL)溶液中加入乙二胺10ml,混合物25搅拌5h;TLC(DCM/MeOH=10/1)显示反应完毕,原料消失;将反应完旋干,甲基叔丁基醚(10ml)打浆三次,静置后倒出澄清液得不溶物,不溶物油泵拉干得到3.3g粗品11J。
步骤7将粗品11J(3g,10.7mmol)溶于50ml二氯甲烷中,加入11K(16.1mmol,4.93g)及DIEA,混合物25度反应16h。TLC(PE/EA=1/1)显示反应完全。旋干溶剂,加1N的盐酸(50ml),EA(50ml)淬取三次,无水硫酸钠干燥,有机相旋干,用MTBE(20ml)打浆,过滤 得到2.62g白色粉末11L,产率为52%。
步骤8氩气保护下,将11E(150mg,0.27mmol)溶于无水DMF,加入11L(0.41mmol,193mg),HATU,DIEA及DMAP,在25℃下反应1小时,LCMS显示原料反应完全。将反应液滴加到pH=4的柠檬酸水溶液(15ml)中,析出黄色固体,滤干,经prep-HPLC(0.1%TFA)制备冻干后得17mg黄色固体11,收率:6.3%。LC-MS:[M+H]=1011.11。
1H NMR(400MHz,Methanol-d4)δ7.39(d,J=10.1Hz,1H),7.32–7.26(m,4H),7.26–7.21(m,1H),6.79(s,2H),6.19(dd,J=10.1,2.0Hz,1H),6.01(s,1H),4.84–4.81(m,1H),4.80–4.70(m,2H),4.61(s,1H),4.55–4.46(m,2H),4.44–4.40(m,1H),4.40–4.31(m,2H),3.90(d,J=16.9Hz,1H),3.84(d,J=5.5Hz,4H),3.76(d,J=17.0Hz,1H),3.48(t,J=7.1Hz,2H),3.24(dd,J=13.9,5.7Hz,1H),3.02(dd,J=13.9,9.4Hz,1H),2.70–2.60(m,1H),2.38(d,J=13.7Hz,1H),2.27(t,J=7.5Hz,2H),2.25–2.16(m,1H),2.16–2.07(m,1H),1.95–1.82(m,2H),1.79–1.68(m,6H),1.68–1.51(m,9H),1.48(s,3H),1.38–1.28(m,2H),1.26–1.04(m,6H),1.01–0.91(m,4H)
制备例1.14
在37℃条件下,向抗体Adalimumab(Humira,其轻链可包含SEQ ID NO:18所示的氨基酸序列,且其重链可包含SEQ ID NO:20所示的氨基酸序列)的PBS缓冲水溶液(pH=7.0的0.05M的PBS缓冲水溶液;2.5mL,9.96mg/mL,0.166μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.066mL,0.664μmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/mL。
将化合物LP-I-1(1.01mg,0.996μmol)溶解于0.20mL DMA中,加入到上述溶液中, 置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物ADC-I-743-1(4.64mg/mL,2.8mL)。收率:52%。
N
a-I经LC-MS检测,为4.21。
制备例1.15
在37℃条件下,向抗体BIIB059抗体(所述轻链可包含SEQ ID NO:17所示的氨基酸序列,且所述重链可包含SEQ ID NO:19所示的氨基酸序列)的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液1.1mL,7.5mg/mL,0.055μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.019mL,0.193μmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/mL往下反应。
将化合物LP-I-1(0.57mg,0.55μmol)溶解于0.30mL DMA中,加入到上述溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物ADC-I-743-2(0.54mg/mL,3.85mL)。收率:26%。
N
a-I经LC-MS检测,为2.96。
制备例1.16
在37℃条件下,向抗体8c11(所述轻链可包含SEQ ID NO:41所示的氨基酸序列,且所述重链可包含SEQ ID NO:42所示的氨基酸序列)的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液5.65mL,5.8mg/mL,0.22μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.092mL,0.924μmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,直接往下反应。
将化合物LP-I-1(2.22mg,2.2μmol)溶解于0.69mL DMA中,加入到上述溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物ADC-I-743-3(3.82mg/mL,7.33mL)。收率:83%。
N
a-I经LC-MS检测,为3.83。
制备例1.17
在37℃条件下,向抗体Adalimumab(Humira,其轻链可包含SEQ ID NO:18所示的氨基酸序列,且其重链可包含SEQ ID NO:20所示的氨基酸序列)的PBS缓冲水溶液(pH=7.0的0.05M的PBS缓冲水溶液;4.92mL,9.96mg/mL,0.327μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.114mL,1.14μmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,稀释至5.0mg/mL。
将化合物LP-I-16(4.23mg,4.91μmol)溶解于0.50mL DMA中,加入到上述溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物ADC-I-16-1(3.34mg/mL,14.4mL)。收率:98%。
N
a-I经LC-MS检测,为3.92。
制备例1.18
在37℃条件下,向抗体8c11抗体(所述轻链可包含SEQ ID NO:41所示的氨基酸序列,且所述重链可包含SEQ ID NO:42所示的氨基酸序列)的PBS缓冲水溶液(pH=7.0的0.05M的PBS缓冲水溶液;5.82mL,5.8mg/mL,0.225μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.095mL,0.945μmol),置于水浴振荡器,于37℃振荡反应3小时,停止反应;将反应液用水浴降温至25℃,直接向下反应。
将化合物LP-I-16(2.92mg,3.38μmol)溶解于0.6mL DMA中,加入到上述溶液中,置于水浴振荡器,于25℃振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH=5.5的0.05M的组氨酸缓冲水溶液,含0.001M的EDTA),得到偶联物ADC-I-16-2(2.71mg/mL,10.3mL)。收率:83%。
N
a-I经LC-MS检测,为3.94。
实施例2
检测例2.1 GRE活性测定
人和小鼠跨膜TNF-αGRE报道细胞系的产生
为了产生亲本细胞系,在37℃,5%CO
2下,在24小时内,将K562细胞以每孔500,000个细胞接种到具有2mL的完全生长培养基(RPMI,10%FBS,1%L-谷氨酰胺,1%丙酮酸钠和1%MEMNEAA(非必需氨基酸溶液))的6孔培养皿((柯仕达)Costar:3516)上。第二天,将1.5μg的pGL4.36[Luc2P/MMTV/Hygro](Promega)和3uL的PLUS试剂(Invitrogen))稀释到244μL的Opti-MEM(Gibco:31985-070)中,并在室温下孵育15分钟。pGL4.36[luc2P/MMTV/Hygro]载体含有鼠乳腺肿瘤病毒长末端重复序列,其响应于若干种核受体(例如糖皮质激素受体和雄激素受体)的激活而驱动荧光素酶报告基因luc2P的转录。在孵育后,将稀释的DNA溶液与1∶1脂转染胺(Lipofectamine)LTX溶液(13.2μL+256.8μLOpti-MEM)进行预孵育,并在室温下孵育25分钟以形成DNA-脂转染胺LTX复合物。在孵育后,将500μL的DNA-脂转染胺复合物直接添加到含有细胞的孔中。将K562细胞在37℃,5%CO
2下转染24小时。在孵育后,将细胞用3mL的PBS洗涤,并用含有125μg/mL的潮霉素B的完全生长培养基选择两周。产生“K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]”细胞。
为了产生鼠跨膜TNF-αGRE报告细胞,在37℃,5%CO
2下,在24小时内,将亲本细胞K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]以每孔500,000个细胞接种到含有2mL的完全生长培养基(RPMI,10%FBS,1%L-谷氨酰胺,1%丙酮酸钠和1%MEMNEAA)的6孔培养皿上。第二天,将3μg的编码未标记的小鼠TNF的mFL_TNFαDNA和3μL的PLUS试剂(英杰公司:10964-021)稀释到244μL的Opti-MEM(Gibco:31985-070)中,并在室温下孵育15分钟。在孵育后,将稀释的DNA溶液用1∶1脂转染胺LTX溶液)(13.2μL+256.8μLOpti-MEM)预孵育,并在室温下孵育25分钟,以形成DNA-脂转染胺LTX复合物。在孵育后,将500μL的DNA-脂转染胺复合物直接添加到含有细胞的孔中。将亲本K562pGL4.36\[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]细胞在37℃,5%CO
2下转染24小时。在孵育后,将细胞用3mL的PBS洗涤,并用含有125μg/mL的潮霉素B(英杰公司:10687-010)和250μg/mLG418(Gibco:10131-027)的完全生长培养基选择两周。产生“K562小鼠FL- TNFαGRE(pGL4.36[luc2P/MMTV/Hygro])”细胞。
为了产生人跨膜TNF-αGRE报告细胞系,用质粒hTNFδ1-12C-MycpcDNA3.1(-)质粒构建体来转染亲本细胞K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]。所述质粒是pcDNA3.1(赛默飞世尔,目录号V79020),其编码tace抗性跨膜TNF。(参见PerezC等人,《细胞(Cell)》63(2):251-8(1990),其讨论了tace抗性跨膜TNF。)。产生“K562人TNFδ1-12GRE(pGL4.36[luc2P/MMTV/Hygro])”细胞。然后将这些细胞系用于在随后的实例中描述的TNF-α报告测定中。
将K562亲本GRE细胞(“K562pGL4.36[Luc2P/MMTV/Hygro]_pGL4.75[hRLuc/CMV]”细胞),和GRE-小鼠TNF-α细胞(“K562小鼠FL-TNFαGRE(pGL4.36[luc2P/MMTV/Hygro])”细胞)或GRE-人TNF-α细胞(“K562人TNFδ1-12GRE(pGL4.36[luc2P/MMTV/Hygro])”细胞),以每孔50,000个细胞接种到96孔板上。将本申请配体药物偶联物(ADC)用培养基以3X系列稀释后加入上述96孔板中,在37℃,5%CO
2下孵育48小时。用荧光素酶测定系统处理后分析发光。使用四参数曲线拟合分析数据以产生EC
50值。将最大活化%归一化为100nM地塞米松。本申请配体药物偶联物(ADC)在小鼠跨膜TNFαGRE报告测定中测体外活性;和在本申请配体药物偶联物(ADC)在人跨膜TNFαGRE报告测定中测体外活性
结果显示,本申请配体药物偶联物(ADC)具有影响细胞GRE激活水平的能力,本申请配体药物偶联物(ADC)可以影响糖皮质激素介导的信号通路的激活水平。
检测例2.2脂多糖(LPS)诱导细胞因子释放及下游信号检测
原代人外周血单核细胞(PBMC)在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中。然后将细胞在37℃和5%CO
2下用不同浓度ADC孵育4小时。用一定浓度脂多糖(Lipopolysaccharides,LPS)等刺激物处理一定时间。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-6和IL-1β等细胞因子浓度及磷酸化STAT1水平。
结果显示,本申请配体药物偶联物(ADC)具有影响PBMC细胞释放细胞因子的能力,如IL-6和IL-1β等,以及磷酸化STAT1的能力。
检测例2.3接触性超敏反应模型中的生物活性测定
在急性接触性超敏反应模型中评估ADC,所述模型是通过应用敏化剂(异硫氰酸荧光素, FITC),使用迟发型超敏反应(delayed type hypersensitivity,DTH)响应(T细胞驱动)引发急性皮肤炎症。通过减少耳朵肿胀的能力来测量本申请配体药物偶联物(ADC)的药效。包括检测生物标记物,例如类固醇、皮质酮和前胶原1型N-末端前肽(P1NP),以评估本申请配体药物偶联物(ADC)分别对下丘脑-垂体-肾上腺(HPA)轴和骨转换(骨吸收和骨形成)的影响。
(1)耳朵肿胀检测
在第0天,将小鼠置于全身麻醉下并剃毛腹部。使用微量移液器,腹腔注射400μL的FITC溶液(1∶1丙酮∶DBP(邻苯二甲酸二丁酯)中的1.5%溶液)对小鼠进行致敏。6天后,用FITC进行耳注射前1小时,小鼠进行给药(对照组溶剂或治疗组本申请配体药物偶联物)。对于耳注射,将小鼠置于全身麻醉下,在右耳注射20μl的FITC进行再次致敏。再次致敏24小时后,小鼠全身麻醉下,通过游标卡尺测量耳朵厚度。计算致敏耳朵和未致敏耳朵之间的差异。
结果显示,本申请配体药物偶联物(ADC)具有影响耳部皮肤肿胀的能力,本申请配体药物偶联物(ADC)可以用于预防和/或治疗炎症的疾病和或症状。
(2)释放的游离类固醇和内源性皮质酮、血浆P1NP的定量检测
耳致敏72小时后,小鼠以1mpk(mg/kg)腹腔注射ACTH(促肾上腺皮质激素),并在ACTH给药后30分钟终末放血。收集血浆并分析前胶原1型N-末端前肽(P1NP)、皮质酮、游离类固醇和大分子水平。
在小鼠血浆中以多种(例如8种)不同浓度水平的终浓度为0.03nM至0.1μM来制备类固醇的校准曲线。在PBS缓冲液中的70mg/mL牛血清白蛋白溶液中,制备从0.3nM至1μM最终皮质酮浓度范围的皮质酮校准曲线。将含有0.1%甲酸的160μL MeCN(乙腈)的溶液添加到40μL的待测血浆样品或校准标准品中。上清液用蒸馏水稀释,并注入30μL的最终样品溶液用于LC/MS分析。
胰蛋白酶消化后,在LCMS平台上进行血浆前胶原1型N-末端前肽(P1NP)的定量。作为一种特殊的Ⅰ型胶原蛋白沉淀指示剂,P1NP水平反映成骨细胞活性和骨形成的状态。通过添加MeCN/0.1M碳酸氢铵/DTT(二硫苏糖醇)混合物使血浆样品部分沉淀并完全还原。收集上清液,并通过添加碘乙酸烷基化。烷基化的蛋白质通过胰蛋白酶消化,并且通过LC/MS分析所得的胰蛋白酶酶解肽。
结果显示,本申请配体药物偶联物(ADC)对于游离类固醇和内源性皮质酮、血浆P1NP水平几乎没有影响,本申请配体药物偶联物(ADC)具有生物安全性。
检测例2.4胶原诱导的关节炎模型中的生物活性测定
胶原诱导的关节炎(CIA)模型中评估本申请配体药物偶联物(ADC)的药效。
雄性DBA/1J小鼠获自杰克逊实验室(Jackson Labs)。小鼠在6至8周龄时使用。将所有动物在12小时的明/暗循环下,在恒定的温度和湿度下,自由饮食饮水。监测体重和状况,并且如果呈现出>20%的体重减轻,则对动物实施安乐死。
用100μL的含有100μg的溶解在0.1N乙酸中的II型牛胶原蛋白和200μg的热灭活结核分枝杆菌H37Ra(完全弗氏佐剂,Difco,Laurence,KS)的乳剂在尾部基部皮内(i.d.皮内注射)免疫雄性DBA/J小鼠。在用胶原蛋白免疫后21天,用PBS中的1mg的酵母多糖A(西格玛,圣路易斯,密苏里州(Sigma,St.Louis,MO))对小鼠进行腹膜注射。在腹膜注射后,每周对小鼠进行3至5次关节炎监测。使用Dyer弹簧卡钳(Dyer spring caliper)(Dyer 310-115)评估后爪的爪肿胀。在疾病的第一个临床体征在第24天与第28天之间登记小鼠,并将其分配为等效关节炎严重程度的组。入选时开始早期治疗性治疗。
对动物在腹膜内注射(i.p.)用在0.9%盐水中的对照抗体(高剂量)或抗本申请配体药物偶联物(ADC)(高和低剂量-mg/kg)给药一次。在给药后24小时和72小时,通过尾部切口收集血液用于抗体暴露。在用于组织病理学的终点时间点收集爪。在终点时间点通过心脏穿刺采集血液,用于全血细胞计数(Sysmex XT-2000iV)并分析细胞因子的水平。统计显著性由ANOVA。
结果显示,与对照抗体或媒空白试剂相比,本申请配体药物偶联物(ADC)具有降低小鼠后爪肿胀的能力,可以呈现出约28天的延长的作用持续时间,本申请配体药物偶联物(ADC)具有降低关节炎严重程度的能力和生物安全性(例如血液安全性)。
检测例2.5脂多糖(LPS)诱导细胞因子释放及下游信号检测
原代人外周血单核细胞(PBMC),采购自Allcells和TPCS,在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中,每孔2×10
6个细胞。然后将细胞在37℃和5%CO
2下用不同浓度本申请所述ADC孵育4小时。向每孔中加入50μL LPS溶液(0.1μg/mL),在37摄氏度下,5%CO
2浓度下孵育24小时。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-10等细胞因子的水平。结果如下表和图1所示。
Adalimumab | ADC-I-743-1 | |
IC 50(nM) | 0.27 | 0.11 |
检测例2.6脂多糖(LPS)诱导细胞因子释放及下游信号检测
原代人外周血单核细胞(PBMC),采购自Allcells和TPCS,在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中,每孔2×10
6个细胞。然后将细胞在37℃和5%CO
2下用不同浓度本申请所述ADC孵育4小时。向每孔中加入50μL LPS溶液(0.1μg/mL),在37摄氏度下,5%CO
2浓度下孵育24小时。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-1β等细胞因子的水平。结果如下表和图2A-2B所示。
Adalimumab | ADC-I-743-1 | |
IC 50(nM) | \ | 4.85 |
检测例2.7脂多糖(LPS)诱导细胞因子释放及下游信号检测
原代人外周血单核细胞(PBMC),采购自Allcells和TPCS,在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中,每孔2×10
6个细胞。然后将细胞在37℃和5%CO
2下用不同浓度本申请所述ADC孵育4小时。向每孔中加入50μL LPS溶液(0.1μg/mL),在37摄氏度下,5%CO
2浓度下孵育24小时。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-1β等细胞因子的水平。结果如图3所示。
检测例2.8接触性超敏反应模型(FITC)中的生物活性测定
在急性接触性超敏反应模型中评估ADC,所述模型是通过应用敏化剂(异硫氰酸荧光素,FITC),使用迟发型超敏反应(delayed type hypersensitivity,DTH)响应(T细胞驱动)引发急性皮肤炎症。通过减少耳朵肿胀的能力来测量本申请配体药物偶联物(ADC)的药效
在第0天,将小鼠置于全身麻醉下并剃毛腹部。使用微量移液器,腹腔注射400μL的FITC溶液(1∶1丙酮∶DBP(邻苯二甲酸二丁酯)中的1.5%溶液)对小鼠进行致敏。6天后,用FITC进行耳注射前1小时,小鼠进行给药(对照组溶剂或治疗组本申请配体药物偶联物)。对于耳注射,将小鼠置于全身麻醉下,在右耳注射20μl的FITC进行再次致敏。再次致敏24小时后,小鼠全身麻醉下,通过游标卡尺测量耳朵厚度。计算致敏耳朵和未致敏耳朵之间的差异。结果如图4所示,本申请配体药物偶联物相比单抗能够显著减轻小鼠耳肿胀程度。
检测例2.9胶原诱导的关节炎模型中的生物活性测定
DBA/1J小鼠获自杰克逊实验室(Jackson Labs)。小鼠在6至8周龄时使用。将所有动物在 12小时的明/暗循环下,在恒定的温度和湿度下,自由饮食饮水。监测体重和状况,并且如果呈现出>20%的体重减轻,则对动物实施安乐死。
用100μL的含有100μg的溶解在0.1N乙酸中的II型牛胶原蛋白和200μg的热灭活结核分枝杆菌H37Ra(完全弗氏佐剂,Difco,Laurence,KS)的乳剂在尾部基部皮内(i.d.皮内注射)免疫雄性DBA/J小鼠。在用胶原蛋白免疫后21天,用PBS中的1mg的酵母多糖A(西格玛,圣路易斯,密苏里州(Sigma,St.Louis,MO))对小鼠进行腹膜注射。在腹膜注射后,每周对小鼠进行3至5次关节炎监测。使用Dyer弹簧卡钳(Dyer spring caliper)(Dyer 310-115)评估后爪的爪肿胀。在疾病的第一个临床体征在第24天与第28天之间登记小鼠,并将其分配为等效关节炎严重程度的组。
对动物在腹膜内注射(i.p.)用在0.9%盐水中的对照抗体(高剂量)或本申请配体药物偶联物(ADC)(7mg/kg和20mg/kg)给药一次。给药后,每2~3天测量一次爪厚度,并根据爪厚度给出评分(每只爪根据肿胀程度评为0~4分,总分为16分)。结果如图5显示,与溶媒空白试剂相比,本申请配体药物偶联物(ADC)具有降低小鼠爪肿胀的能力。
实施例3
检测例3.1人外周血单核细胞IFNα产生的抑制试验
试验目的
检测本申请配体药物偶联物(ADC)对浆细胞样树突状细胞产生IFNα的抑制作用。以不同浓度的配体药物偶联物体外处理浆细胞样树突状细胞,一定时间后对浆细胞样树突状细胞产生的IFNα进行定量检测。根据IC50评价配体药物偶联物的体外活性。
试验方法
1、人外周血单核细胞重悬于RPMI完全培养基,以0.5-1x10
6/孔接种至96孔板,向其中加入梯度稀释的本申请配体药物偶联物。随后向体系中加入固定浓度的刺激物CpG-A或R848或系统性红斑狼疮SLE免疫复合物(Sm/RNP抗原与抗RNP抗体以一定比例混合),37℃过夜培养。收集上清,利用试剂盒检测上清中IFNα的水平。使用非线性回归将剂量响应数据拟合为S形曲线,计算IC
50值。
2、从人外周血单核细胞中利用浆细胞样树突细胞分离试剂盒(Miltenyi)分离浆细胞样树突细胞,悬浮于RPMI完全培养基,以0.5-2x10
5/孔接种至96孔,向其中加入梯度稀释的本申请配体药物偶联物。随后向体系中加入固定浓度的刺激物CpG-A或R848或SLE免疫复 合物(Sm/RNP抗原与抗RNP抗体以一定比例混合),37℃过夜培养。收集上清,利用试剂盒检测上清中IFNα的水平。使用非线性回归将剂量响应数据拟合为S形曲线,计算IC
50值。
结果显示,本申请的配体药物偶联物可以影响浆细胞样树突状细胞产生IFNα的能力。本申请的配体药物偶联物可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
检测例3.2I型干扰素诱导的响应原件信号检测
向HEK293细胞构建转入pHTS-ISRE荧光素报告基因质粒,构建I型干扰素响应信号的报告系统。细胞培养于含有一定浓度FBS和Geneticin的DMEM培养基,向其中加入梯度稀释的配体药物偶联物和一定浓度浆细胞样树突细胞诱导产生的I型干扰素IFN或重组I型干扰素进行孵育。裂解细胞,确定荧光素强度,使用非线性回归将剂量响应数据拟合为S形曲线,计算IC
50值。
结果显示,本申请的配体药物偶联物可以影响I型干扰素诱导的响应原件信号。本申请的配体药物偶联物可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
检测例3.3CpG-A等诱导细胞因子释放及下游信号分子检测
原代人外周血单核细胞(PBMC)在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中。然后将细胞在37℃和5%CO
2下用不同浓度配体药物偶联物进行孵育。用一定浓度CpG-A或其他刺激物处理一定时间。随后将板以1000rpm旋转5分钟,并且将100μL的上清液培养基直接转移到另一个96孔板中,并分析IL-6和IL-1β等细胞因子水平。
向人外周血单核细胞中加入一定浓度的配体药物偶联物进行培养。随后向其中加入一定浓度浆细胞样树突细胞诱导产生的I型干扰素IFN或重组I型干扰素进行孵育。裂解细胞进行电泳和western blot检测,利用抗人STAT1pTY701抗体确定STAT1磷酸化水平。
结果显示,本申请配体药物偶联物(ADC)具有影响PBMC细胞释放细胞因子的能力,以及磷酸化STAT1的能力。
检测例3.4浆细胞样树突细胞异种移植老鼠模型中的药效评估
试验目的
将本申请本申请配体药物偶联物(ADC)作用于人浆细胞样树突细胞异种移植老鼠模型,利用免疫组化,基因转录分析等手段评估配体药物偶联物的体内药效。
试验方法
1、咪喹莫特诱导模型
用4至8周龄的重度免疫缺陷小鼠(CB17/Icr-Prkdcscid/IcrIcoCrl,Charles River),剃毛背部。将5%咪喹莫特乳膏涂抹于小鼠背部,12小时后进行第二次涂抹。随后小鼠腹腔注射一定浓度的本申请配体药物偶联物或对照配体药物偶联物。12小时后向小鼠尾静脉注射1~10x10
5人浆细胞样树突细胞。再经12小时培养后,对小鼠实行安乐死,收集背部皮肤样品,进行检测。
2.博来霉素诱导模型
用4至8周龄的重度免疫缺陷小鼠(CB17/Icr-Prkdcscid/IcrIcoCrl,Charles River),剃毛背部。将一定浓度的博来霉素皮下注射于小鼠背部单一位点,每两天一次持续注射三周。在第一次博来霉素注射的第0,7,14天向小鼠尾静脉注射1~10x10
5人浆细胞样树突细胞。第一次博来霉素注射前24小时向小鼠腹腔注射一定浓度的本申请配体药物偶联物或对照配体药物偶联物,每5天一次注射。
3、检测方法与指标
(1)试剂盒抽提小鼠皮肤细胞RNA并反转录为cDNA,利用Real-time PCR,以对照配体药物偶联物处理小鼠样品为对照,确定配体药物偶联物对I型IFN信号途径应答基因转录的影响。
(2)小鼠皮肤样品用福尔马林固定并包埋于石蜡中,对石蜡以5μM切片,进行苏木精-伊红染色。以Masson染色法鉴定皮肤样品的纤维化程度。以pSTAT1Tyr701抗体进行免疫组化分析。
(3)小鼠皮肤样品经处理后进行FACS分析,根据细胞表面标记物确定其中浆细胞样树突细胞所占比例。
(4)小鼠皮肤样品经处理后利用胶原分析方法进行胶原含量测定。
结果显示,本申请的配体药物偶联物可以影响(1)I型IFN信号途径应答基因转录能力、(2)影响皮肤样品纤维化的程度、(3)影响浆细胞样树突细胞增殖能力和/或(4)影响皮肤样品胶原含量。本申请的配体药物偶联物在体内可以具有抑制炎症的能力,可以用于炎症等疾病和/或病症的预防和/或治疗。
检测例3.5单次给药ADC的药代动力学和毒性研究
试验目的
猴单次静脉滴注本申请配体药物偶联物(ADC)后,考察药物在猴体内的药动学性质,同时观察动物的毒性表现。
试验方法
药代动力学:猴单次静脉滴注不同剂量的本申请配体药物偶联物(ADC)后,连续多个时间点采集血液样品,通过特异性检测方法检测药物在血液中的浓度。
毒性研究:猴单次静脉滴注不同剂量的本申请配体药物偶联物(ADC)后,通过临床观察、体重和摄食量、血液学、血生化、尿液、大体解剖等多个方面考察动物的耐受性,以及药物相关的毒性表现。
结果显示:(1)猴单次静脉滴注本申请配体药物偶联物(ADC)后,游离药物浓度很低,总抗体和本申请配体药物偶联物(ADC)的药代动力学性质相似,表明本申请配体药物偶联物(ADC)在猴中缓慢释放,偶联方式稳定,可以支持临床拟定的给药频率;(2)猴单次静脉滴注本申请配体药物偶联物(ADC)后,动物耐受性良好,未表现出严重或不可耐受的药物相关毒性,表明本申请配体药物偶联物(ADC)的安全性可控,可支持其进一步的临床应用。
检测例3.5人外周血单核细胞产生细胞因子的抑制试验
试验方法
原代人外周血单核细胞(PBMC),采购自Allcells和TPCS,在50mL PBS中洗涤,重悬于具有5%DMSO的FBS(胎牛血清)中,等分并冷冻保存在液氮中直到使用。将PBMC解冻,重悬于有2%FBS和1%青霉素链霉素的细胞培养基(如RPMI细胞培养基)中,并且接种96孔板中,每孔2×10
6个细胞。然后将细胞在37℃和5%CO
2下用不同浓度本申请所述ADC孵育4小时。随后向体系中加入固定浓度的刺激物R848,37℃过夜培养。收集上清,利用试剂盒检测上清中IFNα和TNFα的水平。结果如图6A和图6B所示,本申请ADC可以显著抑制人外周血单核细胞受R848刺激释放细胞因子的能力。
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方案的范围内。
Claims (190)
- 一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中所述化合物包含式(I-A)所示的结构:其中,Tr I包含-(SP I-1) nI-1-,每一个SP I-1各自独立地为-N(R I-1c)-C(R I-1a)(R I-1b)-,每一个R I-1a、R I-1b和R I-1c各自独立地不存在,或每一个R I-1a、R I-1b和R I-1c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=S、-OR I-2、-SR I-2、-N(R I-a)(R I-2b)、-C(=O)R I- 2、-C(=O)OR I-2、-C(=O)C(=O)R I-2、-C(=O)CH 2C(=O)R I-2、-S(=O)R I-2、-S(=O) 2R I-2、-C(=O)N(R I- 2a)(R I-2b)、-SO 2N(R I-2a)(R I-2b)、-OC(=O)R I-2、和-N(R I-2a)SO 2R I-2b;或每一个R I-1a、R I-1b和R I- 1c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R I-1a、R I-1b和R I-1c各自独立地不被取代,或每一个R I-1a、R I-1b和R I-1c各自独立地被至少1个R I-2取代;或每一个R I-1a和R I-1b各自独立地与它们之间的原子一起形成选自以下组的环A I:脂环基、杂环基、芳基和杂芳基,其中每一个环A I各自独立地不被取代,或每一个环A I各自独立地被至少1个R I-2取代;其中,每一个R I-2,R I-2a和R I-2b各自独立地不存在,或每一个R I-2,R I-2a和R I-2b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH 2C(=O)H、-S(=O)H、-S(=O) 2H、-C(=O)NH 2、-SO 2NH 2、-OC(=O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,R I-G1和R I-G2各自独立地选自以下组:氢、卤素和烷基,R I-G3选自以下组:O、S和N;其中,nI-1至少为1。
- 根据权利要求1所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G1为氢,R I-G2为氢。
- 根据权利要求1-2中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G3为O。
- 根据权利要求1-3中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,nI-1为1。
- 根据权利要求1-4中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-1a和R I-1b各自独立地选自以下组:氢、烷基和被至少1个R I-2取代的烷基。
- 根据权利要求1-5中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-1a和R I-1b各自独立地选自以下组:氢和烷基。
- 根据权利要求1-6中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-1a和R I-1b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求1-7中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-1c各自独立地选自以下组:氢、烷基和被至少1个R I-2取代的烷基。
- 根据权利要求1-8中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-1c各自独立地选自以下组:氢和烷基。
- 根据权利要求1-9中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-1c各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求1-10中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-2,R I-2a和R I-2b各自独立地选自以下组:氢和烷基。
- 根据权利要求1-11中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-2,R I-2a和R I-2b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求1-12中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个SP I-1各自独立地选自以下组:-NH-CH 2-、-NH-CH(CH 3)-、-NH-C(CH 3) 2-、-N(CH 3)-CH 2-、-N(CH 3)-CH(CH 3)-和-N(CH 3)-C(CH 3) 2-。
- 根据权利要求1-13中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个SP I-1各自独立地选自以下组:-NH-CH 2-、-NH-CH(CH 3)-、-N(CH 3)-CH 2-、和-N(CH 3)-C(CH 3)-。
- 根据权利要求1-14中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I还包含-SP I-2-,SP I-2为-(C(R I-3a)(R I-3b)) nI-2-,其中,SP I-2的每一个亚甲基单元不被替代;或SP I-2的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy I-1-、-N(R I-3c)C(=O)-、-C(=O)N(R I-3c)-、-C(=O)-、-OC(=O)-、-C(=O)O-、-NR I-3c-、-O-、-S-、-SO-、-SO 2-、-P(R I-3c)-、-P(=O)(R I-3c)-、-N(R I-3c)SO 2-、-SO 2N(R I- 3c)-、-C(=S)-、-C(=NR I-3c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N 2)-,其中,每一个Cy I-1各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个Cy I-1各自独立地不被取代,或每一个Cy I-1各自独立地被至少1个R I-3c取代;其中,每一个R I-3a、R I-3b和R I-3c各自独立地不存在,或每一个R I-3a、R I-3b和R I-3c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OR I-4、-SR I-4、-N(R I- 4a)(R I-4b)、-C(=O)R I-4、-C(=O)OR I-4、-C(=O)C(=O)R I-4、-C(=O)CH 2C(=O)R I-4、-S(=O)R I-4、-S(=O) 2R I-4、-C(=O)N(R I-4a)(R I-4b)、-SO 2N(R I-4a)(R I-4b)、-OC(=O)R I-4、和-N(R I-4a)SO 2R I-4b;或每一个R I-3a、R I-3b和R I-3c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R I-3a、R I-3b和R I-3c各自独立地不被取代,或每一个R I-3a、R I-3b和R I-3c各自独立地被至少1个R I-4取代;或每一个R I-3a和R I-3b各自独立地与它们之间的原子一起形成选自以下组的环B I:脂环基、杂环基、芳基和杂芳基,其中每一个环B I各自独立地不被取代,或每一个环B I各自独立地被至少1个R I-4取代;其中,每一个R I-4,R I-4a和R I-4b各自独立地不存在,或每一个R I-4,R I-4a和R I-4b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(=O)H、 -C(=O)OH、-C(=O)C(=O)H、-C(=O)CH 2C(=O)H、-S(=O)H、-S(=O) 2H、-C(=O)NH 2、-SO 2NH 2、-OC(=O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,nI-2至少为0。
- 根据权利要求15所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,nI-2选自以下组:0、1、2和3。
- 根据权利要求15-16中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-3a,R I-3b和R I-3c各自独立地选自以下组:氢、=O、-OR I-4、-C(=O)R I- 4、烷基和被至少1个R I-4取代的烷基。
- 根据权利要求15-17中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-3a,R I-3b和R I-3c各自独立地选自以下组:氢和烷基。
- 根据权利要求15-18中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-3a,R I-3b和R I-3c各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求15-19中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-4,R I-4a和R I-4b各自独立地选自以下组:氢和烷基。
- 根据权利要求15-20中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-4,R I-4a和R I-4b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求15-21中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R I-3c)C(=O)-、-C(=O)N(R I-3c)-、-C(=O)-、-OC(=O)-、-C(=O)O-、-NR I-3c-和-O-。
- 根据权利要求15-22中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2的至少1个、至少2个或至少3个亚甲基单元各自独立地被选自以下组的基团替代:-C(=O)-、和-NR I-3c-。
- 根据权利要求15-23中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2选自以下组:-(C(R I-3a)(R I-3b)) 2-、-(C(R I-3a)(R I-3b)) 3-、-N(R I-3c)-C(R I-3a)(R I-3b)-C(=O)-、-N(R I-3c)-(C(R I-3a)(R I-3b)) 2-和-N(R I-3c)-(C(R I-3a)(R I-3b)) 3-。
- 根据权利要求15-24中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2选自以下组:-(CH 2) 2-、-(CH 2) 3-、-NH-CH 2-C(=O)-、-N(CH 3)-CH 2-C(=O)-、-NH-(CH 2) 2-、-NH-(CH 2) 3-、-N(CH 3)-(CH 2) 2-和-N(CH 3)-(CH 2) 3-。
- 根据权利要求15-25中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2为氨基酸的残基。
- 根据权利要求15-26中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2为选自以下组氨基酸的残基:苯丙氨酸、异亮氨酸、亮氨酸、色氨酸、缬氨酸、甲硫氨酸、酪氨酸、丙氨酸、苏氨酸、组氨酸、丝氨酸、谷氨酰胺、精氨酸、赖氨酸、天冬酰胺、谷氨酸、脯氨酸、瓜氨酸、半胱氨酸、天冬氨酸、甘氨酸、缬氨酸、丙氨酸和苯丙氨酸。
- 根据权利要求15-27中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-2为选自以下组氨基酸的残基:谷氨酸、赖氨酸、瓜氨酸、甘氨酸和丙氨酸。
- 根据权利要求15-28中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,R I-p选自以下组:H,-CH 3、-CH-(CH 3) 2、-CH 2-CH(CH 3) 2、-CH(CH 3)-CH 2-CH 3、-CH 2-C 6H 5、-C 8NH 6、-CH 2-C 6H 4-OH、-CH 2-COOH、-CH 2-CONH 2、-(CH 2) 2-COOH、-(CH 2) 4-NH 2、-(CH 2) 2-CONH 2、-(CH 2) 2-S-CH 3、-CH 2-OH、-CH(CH 3)-OH、-CH 2-SH、-C 3H 6、-CH 2-C 3H 3N、-(CH 2) 3-NHC(NH)NH 2和-(CH 2) 3-NHCONH 2。
- 根据权利要求15-30中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I还包含-(SP I-3) nI-3-,每一个SP I-3各自独立地选自以下组:-O-、-S-、-C(=O)-、-N(R I-5)-、-O-C(=O)-、-C(=O)-O-、-N(R I-5)-C(=O)-、-N(R I-5)-C(R I-5a)(R I-5b)-、和-N(R I-5)-C(R I-5a)(R I-5b)-S-,其中,每一个R I-5,R I-5a和R I-5b各自独立地不存在,或每一个R I-5,R I-5a和R I-5b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH 2C(=O)H、-S(=O)H、-S(=O) 2H、-C(=O)NH 2、-SO 2NH 2、-OC(=O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,nI-3至少为0。
- 根据权利要求31所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,nI-3为1。
- 根据权利要求31-32中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-5,R I-5a和R I-5b各自独立地选自以下组:氢和烷基。
- 根据权利要求31-33中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-5,R I-5a和R I-5b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求31-34中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-3选自以下组:-O-、-S-、-C(=O)-、-NH-、-N(CH 3)-、-O-C(=O)-、-NH-C(=O)-、-NH-CH 2-、-NH-CH(CH 3)-、-NH-C(CH 3) 2-、-N(CH 3)-CH 2-、-N(CH 3)-CH(CH 3)-、-N(CH 3)-C(CH 3) 2-、-NH-CH 2-S-、-N(CH 3)-CH 2-S-、-NH-CH(CH 3)-S-和-N(CH 3)-CH(CH 3)-S-。
- 根据权利要求31-35中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-3选自以下组:-O-、-S-、-C(=O)-、-NH-、-O-C(=O)-、-C(=O)-O-、-NH-C(=O)-、 -NH-CH 2-、和-NH-CH 2-S-。
- 根据权利要求31-36中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,SP I-3为-O-C(=O)-。
- 根据权利要求31-37中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I还包含-SP I-4-,其中,每一个R I-6,R I-7和R I-8各自独立地不存在,或每一个R I-6,R I-7和R I-8各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(=O)H、-C(=O)OH、-C(=O)C(=O)H、-C(=O)CH 2C(=O)H、-S(=O)H、-S(=O) 2H、-C(=O)NH 2、-SO 2NH 2、-OC(=O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,nI-4和nI-5各自独立地至少为0。
- 根据权利要求38所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-6,R I-7和R I-8各自独立地选自以下组:氢和烷基。
- 根据权利要求38-39中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-6,R I-7和R I-8各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求1-41中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I包含-SP I-2-(SP I-1) nI-1-。
- 根据权利要求1-42中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I包含-(SP I-3) nI-3-SP I-2-(SP I-1) nI-1-。
- 根据权利要求1-43中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I包含-SP I-4-(SP I-3) nI-3-SP I-2-(SP I-1) nI-1-。
- 根据权利要求1-44中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I选自以下组:其中,每一个R I-1a,R I-1b,R I-1c和R I-3c各自独立地选自以下组:氢和C 1-C 6烷基,R I-p选自以下组:H,-CH 3、-CH-(CH 3) 2、-CH 2-CH(CH 3) 2、-CH(CH 3)-CH 2-CH 3、-CH 2-C 6H 5、-C 8NH 6、-CH 2-C 6H 4-OH、-CH 2-COOH、-CH 2-CONH 2、-(CH 2) 2-COOH、-(CH 2) 4-NH 2、-(CH 2) 2-CONH 2、-(CH 2) 2-S-CH 3、-CH 2-OH、-CH(CH 3)-OH、-CH 2-SH、-C 3H 6、-CH 2-C 3H 3N、-(CH 2) 3-NHC(NH)NH 2和-(CH 2) 3-NHCONH 2。
- 根据权利要求1-44中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I选自以下组:其中,R I-p选自以下组:H,-CH 3、-CH-(CH 3) 2、-CH 2-CH(CH 3) 2、-CH(CH 3)-CH 2-CH 3、-CH 2-C 6H 5、-C 8NH 6、-CH 2-C 6H 4-OH、-CH 2-COOH、-CH 2-CONH 2、-(CH 2) 2-COOH、-(CH 2) 4-NH 2、-(CH 2) 2-CONH 2、-(CH 2) 2-S-CH 3、-CH 2-OH、-CH(CH 3)-OH、-CH 2-SH、-C 3H 6、-CH 2-C 3H 3N、-(CH 2) 3-NHC(NH)NH 2和-(CH 2) 3-NHCONH 2。
- 根据权利要求1-47中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Tr I选自以下组:其中,R I-p选自以下组:H,-CH 3、-CH-(CH 3) 2、-CH 2-CH(CH 3) 2、-CH(CH 3)-CH 2-CH 3、-CH 2-C 6H 5、-C 8NH 6、-CH 2-C 6H 4-OH、-CH 2-COOH、-CH 2-CONH 2、-(CH 2) 2-COOH、-(CH 2) 4-NH 2、-(CH 2) 2-CONH 2、-(CH 2) 2-S-CH 3、-CH 2-OH、-CH(CH 3)-OH、-CH 2-SH、-C 3H 6、-CH 2-C 3H 3N、-(CH 2) 3-NHC(NH)NH 2和-(CH 2) 3-NHCONH 2。
- 一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,所述化合物包含选自以下组的结构:其中,R I-p选自以下组:H,-CH 3、-CH-(CH 3) 2、-CH 2-CH(CH 3) 2、-CH(CH 3)-CH 2-CH 3、-CH 2-C 6H 5、-C 8NH 6、-CH 2-C 6H 4-OH、-CH 2-COOH、-CH 2-CONH 2、-(CH 2) 2-COOH、-(CH 2) 4-NH 2、-(CH 2) 2-CONH 2、-(CH 2) 2-S-CH 3、-CH 2-OH、-CH(CH 3)-OH、-CH 2-SH、-C 3H 6、-CH 2-C 3H 3N、-(CH 2) 3-NHC(NH)NH 2和-(CH 2) 3-NHCONH 2。
- 根据权利要求50所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G1为氢,R I-G2为氢。
- 根据权利要求50-51中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G3为O。
- 根据权利要求50-52中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-1选自以下组:氨基参与偶联形成的二价残基或三价残基、巯基参与偶联形成的二价残基或三价残基、和点击化学偶联形成的二价残基或三价残基。
- 根据权利要求55所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-9选自以下组:氢和烷基。
- 根据权利要求55-56中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-9选自以下组:氢和C 1-C 6烷基。
- 根据权利要求50-59中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I还包含L I-2,L I-2不存在,或L I-2包含-X I-,X I为-(C(R I-10a)(R I-10b)) pI-1-,其中,X I的每一个亚甲基单元不被替代;或X I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy I-2-、-N(R I-10c)C(O)-、-C(O)N(R I-10c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR I-10c-、-O-、-S-、-SO-、-SO 2-、-P(R I-10c)-、-P(=O)(R I-10c)-、-N(R I-10c)SO 2-、-SO 2N(R I-10c)-、-C(=S)-、-C(=NR I-10c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N 2)-,其中,每一个Cy I- 2各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个Cy I-2各自独立地不被取代,或每一个Cy I-2各自独立地被至少1个R I-10c取代;其中,每一个R I-10a、R I-10b和R I-10c各自独立地不存在,或每一个R I-10a、R I-10b和R I-10c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OR I-11、-SR I-11、-N(R I-11a)(R I-11b)、-C(O)R I-11、-C(=O)OR I-11、-C(O)C(O)R I-11、-C(O)CH 2C(O)R I-11、-S(O)R I-11、-S(O) 2R I-11、-C(O)N(R I-11a)(R I-11b)、-SO 2N(R I-11a)(R I-11b)、-OC(O)R I-11、和-N(R I-11)SO 2R I-11;或每一个R I-10a、R I-10b和R I-10c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R I-10a、R I-10b和R I-10c各自独立地不被取代,或每一个R I-10a、R I- 10b和R I-10c各自独立地被至少1个R I-11取代;或每一个R I-10a和R I-10b各自独立地与它们之间的原子一起形成选自以下组的环C I:脂环基、杂环基、芳基和杂芳基,其中每一个环C I各自独立地不被取代,或每一个环C I各自独立地被至少1个R I-11取代;其中,每一个R I-11,R I-11a和R I-11b各自独立地不存在,或每一个R I-11,R I-11a和R I-11b各 自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH 2C(O)H、-S(O)H、-S(O) 2H、-C(O)NH 2、-SO 2NH 2、-OC(O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,pI-1至少为0。
- 根据权利要求60所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-1选自以下组:0、1、2、3、4和5。
- 根据权利要求60-61中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-10a、R I-10b和R I-10c各自独立地选自以下组:氢、=O、-OR I-11、-C(O)R I- 11、烷基和被至少1个R I-11取代的烷基。
- 根据权利要求60-62中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-10a、R I-10b和R I-10c各自独立地选自以下组:氢和烷基。
- 根据权利要求60-63中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-10a、R I-10b和R I-10c各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求60-64中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-11,R I-11a和R I-11b各自独立地选自以下组:氢和烷基。
- 根据权利要求60-65中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-11,R I-11a和R I-11b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求60-66中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,X I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R I-10c)C(O)-、-C(O)N(R I-10c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR I-10c-、-S-和-O-。
- 根据权利要求60-67中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,X I的1或2个亚甲基单元各自独立地被选自以下组的基团替代:-C(O)N(R I-10c)-、 -S-、-C(O)-、-OC(O)-、-C(O)O-、和-NR I-10c-。
- 根据权利要求60-68中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,X I选自以下组:-C(O)-、-OC(O)-、-C(O)O-、-NR I-10c-和-C(O)-NH-CH 2-C(R I-10a)(R I- 10b)-S-,每一个R I-10a、R I-10b和R I-10c各自独立地选自以下组:氢和烷基。
- 根据权利要求60-69中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,X I选自以下组:-C(O)-和-C(O)-NH-CH 2-C(CH 3) 2-S-。
- 根据权利要求71所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-2选自以下组:0、1、2、3、4和5。
- 根据权利要求71-72中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-p选自以下组:氨基酸、氨基醇、氨基醛和多胺。
- 根据权利要求71-73中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-p选自以下组:天冬氨酸、谷氨酸、组氨酸、赖氨酸,精氨酸,丝氨酸,半胱氨酸,苏氨酸,和酪氨酸。
- 根据权利要求71-74中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-p选自以下组:天冬氨酸,谷氨酸和赖氨酸。
- 根据权利要求71-75中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-p为:其中,每一个R I-12a和R I-12b各自独立地不存在,或每一个R I-12a和R I-12b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH 2C(O)H、-S(O)H、-S(O) 2H、-C(O)NH 2、-SO 2NH 2、-OC(O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;B I-p选自以下组:-NH-、-N(CH 3)-、-C(O)-、和-O-;其中,pI-p至少为0。
- 根据权利要求76所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-p选自以下组:0、1、2、3和4。
- 根据权利要求76-77中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-12a和R I-12b各自独立地选自以下组:氢和烷基。
- 根据权利要求76-78中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-12a和R I-12b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求71-80中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PEG I包含-(PX I-(CH 2CH 2O) pI-3) pI-4-,其中,pI-3和pI-4各自独立地至少为1,其中,PX I包含-(C(R I-13a)(R I-13b)) pI-5-,其中,PX I的每一个亚甲基单元不被替代,或PX I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy I-3-、-N(R I-13c)C(O)-、-C(O)N(R I-13c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR I-13c-、-O-、-S-、-SO-、-SO 2-、-P(R I-13c)-、-P(=O)(R I-13c)-、-N(R I-13c)SO 2-、-SO 2N(R I-13c)-、-C(=S)-、-C(=NR I-13c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N 2)-,其中,每一个-Cy I-3-各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个-Cy I-3-各自独立地不被取代,或每一个-Cy I-3-各自独立地被至少1个R I-13c取代;其中,每一个R I-13a、R I-13b和R I-13c各自独立地不存在;或每一个R I-13a、R I-13b和R I-13c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OR I-14、-SR I-14、-N(R I-14a)(R I-14b)、-C(O)R I-14、-C(=O)OR I-14、-C(O)C(O)R I-14、-C(O)CH 2C(O)R I-14、-S(O)R I-14、-S(O) 2R I-14、-C(O)N(R I-14a)(R I-14b)、-SO 2N(R I-14a)(R I-14b)、-OC(O)R I-14、和-N(R I-14)SO 2R I-14;或每一个R I-13a、R I-13b和R I-13c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R I-13a、R I-13b和R I-13c各自独立地不被取代,或每一个R I-13a、R I- 13b和R I-13c各自独立地被至少1个R I-14取代;或每一个R I-13a和R I-13b各自独立地与它们之间的原子一起形成选自以下组的环D I:脂环基、杂环基、芳基和杂芳基,其中每一个环D I各自独立地不被取代,或每一个环D I各自独立地被至少1个R I-14取代;其中,每一个R I-14,R I-14a和R I-14b各自独立地不存在,或每一个R I-14,R I-14a和R I-14b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH 2C(O)H、-S(O)H、-S(O) 2H、-C(O)NH 2、-SO 2NH 2、-OC(O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,pI-5至少为0。
- 根据权利要求81所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-5选自以下组:0、1、2、3、4和5。
- 根据权利要求81-82中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-13a、R I-13b和R I-13c各自独立地选自以下组:氢、=O、-OR I-14、-C(O)R I- 14、烷基和被至少1个R I-14取代的烷基。
- 根据权利要求81-83中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-13a、R I-13b和R I-13c各自独立地选自以下组:氢和烷基。
- 根据权利要求81-84中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-13a、R I-13b和R I-13c各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求81-85中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-14,R I-14a和R I-14b各自独立地选自以下组:氢和烷基。
- 根据权利要求81-86中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-14,R I-14a和R I-14b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求81-87中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PX I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R I-13c)C(O)-、-C(O)N(R I-13c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR I-13c-、和-O-。
- 根据权利要求81-88中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PX I的1或2个亚甲基单元各自独立地被选自以下组的基团替代:-C(O)-、-OC(O)-、-C(O)O-、和-NR I-13c-。
- 根据权利要求81-89中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PX I选自以下组:-C(O)-和-NR I-13c-。
- 根据权利要求81-90中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PX I选自以下组:-C(O)-和-NH-。
- 根据权利要求81-91中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-3选自以下组:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、和24。
- 根据权利要求81-92中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-3选自以下组:4、6、8、10、12和24。
- 根据权利要求81-93中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-3选自以下组:8、9、10、12和24。
- 根据权利要求81-94中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-4选自以下组:1、2、3、4和5。
- 根据权利要求81-95中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PEG I还包含-PZ I,PZ I不存在,或PZ I选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OR I-15、-SR I-15、-N(R I-15a)(R I-15b)、-C(O)R I-15、-C(=O)OR I-15、-C(O)C(O)R I- 15、-C(O)CH 2C(O)R I-15、-S(O)R I-15、-S(O) 2R I-15、-C(O)N(R I-15a)(R I-15b)、-SO 2N(R I-15a)(R I-15b)、-OC(O)R I-15、和-N(R I-15)SO 2R I-15;或PZ I选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中PZ I不被取代,或PZ I被至少1个R I-15取代;其中,每一个R I-15,R I-15a和R I-15b各自独立地不存在,或每一个R I-15,R I-15a和R I-15b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH 2C(O)H、-S(O)H、-S(O) 2H、-C(O)NH 2、-SO 2NH 2、-OC(O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基。
- 根据权利要求96所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PZ I选自以下组:氢、烷基和被至少1个R I-15取代的烷基。
- 根据权利要求96-97中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PZ I选自以下组:氢、C 1-C 6烷基和被至少1个R I-15取代的C 1-C 6烷基。
- 根据权利要求96-98中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-15选自以下组:-OH、-C(O)H、-NH 2、和-C(=O)OH。
- 根据权利要求96-99中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,PZ I选自以下组:氢、-CH 2-CH 2-C(O)OH和甲基。
- 根据权利要求60-102中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2还包含-Y I-,Y I为-(OCH 2CH 2) pI-6-O pI-7-,pI-6和pI-7各自独立地至少为0。
- 根据权利要求103所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-7选自以下组:0和1。
- 根据权利要求103-104中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-6选自以下组:0、1、2、3、4、5、6、7、8、9、10、11和12。
- 根据权利要求103-105中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-6选自以下组:3、4、5、6、8、10和12。
- 根据权利要求103-106中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-6选自以下组:3、4、5、6、7和8。
- 根据权利要求103-107中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-6选自以下组:3、5和7。
- 根据权利要求103-108中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Y I选自以下组:-(OCH 2CH 2) 3-、-(OCH 2CH 2) 4-、-(OCH 2CH 2) 5-、-(OCH 2CH 2) 6-、-(OCH 2CH 2) 7-和-(OCH 2CH 2) 8-。
- 根据权利要求103-109中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Y I选自以下组:-(OCH 2CH 2) 3-、-(OCH 2CH 2) 5-和-(OCH 2CH 2) 7-。
- 根据权利要求60-110中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2还包含-Z I-,Z I为-(C(R I-16a)(R I-16b)) pI-8-,其中,Z I的每一个亚甲基单元不被替代;或Z I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-Cy I-4-、-N(R I-16c)C(O)-、-C(O)N(R I-16c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR I-16c-、-O-、-S-、-SO-、-SO 2-、-P(R I-16c)-、-P(=O)(R I-16c)-、-N(R I-16c)SO 2-、-SO 2N(R I-16c)-、-C(=S)-、-C(=NR I-16c)-、-N=N-、-C=C-、-C=N-、-N=C-和-C(=N 2)-,其中,每一个Cy I- 4各自独立地选自以下组:脂环基、杂环基、芳基和杂芳基,每一个Cy I-4各自独立地不被取代,或每一个Cy I-4各自独立地被至少1个R I-16c取代;其中,每一个R I-16a、R I-16b和R I-16c各自独立地不存在;或每一个R I-16a、R I-16b和R I-16c各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OR I-17、-SR I-17、-N(R I-17a)(R I-17b)、-C(O)R I-17、-C(=O)OR I-17、-C(O)C(O)R I-17、-C(O)CH 2C(O)R I-17、-S(O)R I-17、-S(O) 2R I-17、-C(O)N(R I-17a)(R I-17b)、-SO 2N(R I-17a)(R I-17b)、-OC(O)R I-17、和-N(R I-17)SO 2R I-17;或每一个R I-16a、R I-16b和R I-16c各自独立地选自以下组:烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基,其中每一个R I-16a、R I-16b和R I-16c各自独立地不被取代,或每一个R I-16a、R I- 16b和R I-16c各自独立地被至少1个R I-17取代;或每一个R I-16a和R I-16b各自独立地与它们之间的原子一起形成选自以下组的环E I:脂环基、杂环基、芳基和杂芳基,其中每一个环E I各自独立地不被取代,或每一个环E I各自独立地被至少1个R I-17取代;其中,每一个R I-17,R I-17a和R I-17b各自独立地不存在,或每一个R I-17,R I-17a和R I-17b各自独立地选自以下组:氢、氕、氘、氚、卤素、-NO 2、-CN、=O、=S、-OH、-SH、-NH 2、-C(O)H、-C(=O)OH、-C(O)C(O)H、-C(O)CH 2C(O)H、-S(O)H、-S(O) 2H、-C(O)NH 2、-SO 2NH 2、-OC(O)H、-N(H)SO 2H、烷基、烯基、炔基、脂环基、杂环基、芳基和杂芳基;其中,pI-8至少为0。
- 根据权利要求111所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,pI-8选自以下组:0、1、2、3、4、5、6和7。
- 根据权利要求111-112中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-16a、R I-16b和R I-16c各自独立地选自以下组:氢、=O、-OR I-17、-C(O)R I- 17、烷基和被至少1个R I-17取代的烷基。
- 根据权利要求111-113中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-16a、R I-16b和R I-16c各自独立地选自以下组:氢和烷基。
- 根据权利要求111-114中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-16a、R I-16b和R I-16c各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求111-115中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-17,R I-17a和R I-17b各自独立地选自以下组:氢和烷基。
- 根据权利要求111-116中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,每一个R I-17,R I-17a和R I-17b各自独立地选自以下组:氢和C 1-C 6烷基。
- 根据权利要求111-117中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Z I的至少1个亚甲基单元各自独立地被选自以下组的基团替代:-N(R I-16c)C(O)-、-C(O)N(R I-16c)-、-C(O)-、-OC(O)-、-C(O)O-、-NR I-16c-、和-O-。
- 根据权利要求111-118中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Z I的1或2个亚甲基单元各自独立地被选自以下组的基团替代:-C(O)N(R I-16c)-、-C(O)-、-OC(O)-、-C(O)O-、和-NR I-16c-。
- 根据权利要求111-119中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Z I选自以下组:-NR I-16c-、-NR I-16c-(C(R I-16a)(R I-16b)) 2-、-(C(R I-16a)(R I-16b)) 2、-(C(R I- 16a)(R I-16b)) 5、-(C(R I-16a)(R I-16b)) 2-C(O)-,-(C(R I-16a)(R I-16b)) 5-C(O)-,-(C(R I-16a)(R I-16b)) 2-C(O)-NR I- 16c-(C(R I-16a)(R I-16b)) 2-,-(C(R I-16a)(R I-16b)) 2-NR I-16c-C(O)-(C(R I-16a)(R I-16b)) 2-,-C(O)-(C(R I-16a)(R I- 16b)) 2-C(O)-NR I-16c-(C(R I-16a)(R I-16b)) 2-和-C(R I-16a)(R I-16b)-O-C(O)-NR I-16c-(C(R I-16a)(R I-16b)) 2-。
- 根据权利要求111-120中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Z I选自以下组:-NH-、-(CH 2) 2-,-(CH 2) 5-,(CH 2) 2-C(O)-,-(CH 2) 4-C(O)-,-(CH 2) 5-C(O)-,-(CH 2) 2-C(O)-NH-(CH 2) 2-,-C(O)-(CH 2) 2-C(O)-NH-(CH 2) 2-,-NH-(CH 2) 2-和-CH 2-O-C(O)-NH-(CH 2) 2-。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2不存在。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2包含-Z I-X I-、-Z I-或-X I-。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2包含-Z I-X I-。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2包含-Z I-Y I-X I-、-Z I-Y I-、-Y I-X I-或-Y I-。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2包含-Z I-Y I-X I-。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2包含-Z I-B I-X I-、-Z I-B I-、-B I-X I-或-B I-。
- 根据权利要求60-121中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-2包含-Z I-B I-或-B I-。
- 根据权利要求50-131中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I还包含L I-3,L I-3为多肽残基。
- 根据权利要求132所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含至少1个氨基酸残基。
- 根据权利要求132-133中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含选自以下组的疏水氨基酸的残基:苯丙氨酸(F),异亮氨酸(I),亮氨酸(L),色氨酸(W),缬氨酸(V),甲硫氨酸(M),酪氨酸(Y),丙氨酸(A),苏氨酸(T),和组氨酸(H)。
- 根据权利要求132-134中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含选自以下组的亲水氨基酸的残基:丝氨酸(S),谷氨酰胺(Q),精氨酸(R),赖氨酸(K),天冬酰胺(N),谷氨酸(E),脯氨酸(P),瓜氨酸(C)和天冬氨酸(D)。
- 根据权利要求132-135中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含甘氨酸(G)。
- 根据权利要求132所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3不包含亲水氨基酸的残基。
- 根据权利要求137所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含选自以下组的氨基酸的残基:甘氨酸(G)、缬氨酸(V)、丙氨酸(A)和苯丙氨酸(F)。
- 根据权利要求137-138中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)、甘氨酸-甘氨酸-丙氨酸-甘氨酸 (GGAG)、丙氨酸-丙氨酸-丙氨酸-甘氨酸(AAAG)、甘氨酸-甘氨酸-甘氨酸-甘氨酸(GGGG)、甘氨酸-甘氨酸-丙氨酸(GGA)、甘氨酸-丙氨酸-甘氨酸(GAG)、甘氨酸-苯丙氨酸-甘氨酸(GFG)、缬氨酸-丙氨酸-甘氨酸(VAG)、丙氨酸-丙氨酸-甘氨酸(AAG)、丙氨酸-丙氨酸-丙氨酸(AAA)、缬氨酸-丙氨酸(VA)、丙氨酸-丙氨酸(AA)、甘氨酸-丙氨酸(GA)、和丙氨酸-甘氨酸(AG)。
- 根据权利要求137-139所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)和丙氨酸-丙氨酸(AA)。
- 根据权利要求132中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含至少1个亲水氨基酸的残基。
- 根据权利要求141所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含选自以下组的氨基酸的残基:甘氨酸(G)、缬氨酸(V)、丙氨酸(A)、瓜氨酸(C)、赖氨酸(K)、谷氨酸(E)和天冬氨酸(D)。
- 根据权利要求141-142中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:谷氨酸-丙氨酸-甘氨酸-甘氨酸(EAGG)、甘氨酸-谷氨酸-丙氨酸-甘氨酸(GEAG)、甘氨酸-天冬氨酸-丙氨酸-甘氨酸(GDAG)、甘氨酸-天冬氨酸-甘氨酸-甘氨酸(GDGG)、甘氨酸-谷氨酸-甘氨酸-甘氨酸(GEGG)、谷氨酸-甘氨酸-甘氨酸(EGG)、谷氨酸-丙氨酸-甘氨酸(EAG)、天冬氨酸-丙氨酸-甘氨酸(DAG)、天冬氨酸-甘氨酸-甘氨酸(DGG)、缬氨酸-赖氨酸-甘氨酸(VKG)、甘氨酸-天冬氨酸-甘氨酸(GDG)、甘氨酸-天冬氨酸-丙氨酸(GDA)、甘氨酸-谷氨酸-甘氨酸(GEG)、缬氨酸-瓜氨酸-甘氨酸(VCG)、甘氨酸-谷氨酸-丙氨酸(GEA)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)、缬氨酸-瓜氨酸(VC)、甘氨酸-谷氨酸(GE)、天冬氨酸-甘氨酸(DG)、天冬氨酸-丙氨酸(DA)、甘氨酸-天冬氨酸(GD)和缬氨酸-赖氨酸(VK)。
- 根据权利要求141-143中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:甘氨酸-谷氨酸-甘氨酸(GEG)、谷氨酸-丙氨酸-甘氨酸(EAG)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)和甘氨酸-谷氨酸(GE)。
- 根据权利要求132所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3不包含疏水氨基酸的残基。
- 根据权利要求145所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3包含选自以下组的氨基酸的残基:甘氨酸(G)、谷氨酸(E)和天冬氨酸(D)。
- 根据权利要求145-146中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:甘氨酸-谷氨酸(GE)、甘氨酸-甘氨酸(GG)、天冬氨酸-甘氨酸(DG)、甘氨酸-天冬氨酸(GD)、谷氨酸-甘氨酸(EG)、甘氨酸-天冬氨酸-甘氨酸(GDG)、天冬氨酸-甘氨酸-甘氨酸(DGG)、甘氨酸-谷氨酸-甘氨酸(GEG)和甘氨酸-天冬氨酸-甘氨酸-甘氨酸(GDGG)。
- 根据权利要求145-147中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:谷氨酸-甘氨酸(EG)、谷氨酸-丙氨酸(EA)、甘氨酸-谷氨酸(GE)、缬氨酸-瓜氨酸(VC)、缬氨酸-丙氨酸(VA)、丙氨酸-丙氨酸(AA)、谷氨酸-丙氨酸-甘氨酸(EAG)、谷氨酸-甘氨酸-甘氨酸(EGG)、甘氨酸-谷氨酸-甘氨酸(GEG)、丙氨酸-丙氨酸-甘氨酸(AAG)、丙氨酸-丙氨酸-丙氨酸(AAA)、缬氨酸-丙氨酸-甘氨酸(VAG)、缬氨酸-瓜氨酸-甘氨酸(VCG)、缬氨酸-赖氨酸-甘氨酸(VKG)、甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)、甘氨酸-甘氨酸-甘氨酸-甘氨酸(GGGG)、甘氨酸-谷氨酸-甘氨酸-甘氨酸(GEGG)、和甘氨酸-谷氨酸-丙氨酸-甘氨酸(GEAG)。
- 根据权利要求145-148中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中L I-3选自以下组:丙氨酸-丙氨酸(AA)、谷氨酸-丙氨酸-甘氨酸(EAG)、甘氨酸-谷氨酸-甘氨酸(GEG)、谷氨酸-丙氨酸(EA)、谷氨酸-甘氨酸(EG)和甘氨酸-谷氨酸(GE)。
- 根据权利要求150所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G3为O。
- 根据权利要求150-151中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G1为氢,R I-G2为氢。
- 根据权利要求150-152中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I为权利要求50-149中任一项所述的L I。
- 根据权利要求150-153中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Ab I包含抗体或其抗原结合片段。
- 根据权利要求154所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,所述抗体选自以下组:鼠源抗体、嵌合抗体、人源化抗体和全人源抗体。
- 根据权利要求154所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,所述抗原结合片段选自以下组:Fab,Fab′,Fv片段,F(ab') 2,F(ab) 2,scFv,di-scFv,VHH和dAb。
- 根据权利要求150-156中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,Ab I靶向选自以下组的靶点:AXL,BAFFR,BCMA,BCR–列表组分(BCR–list components),BDCA2,BDCA4,BTLA,BTNL2 BTNL3,BTNL8,BTNL9,C10orf54,CCR1,CCR3,CCR4,CCR5,CCR6,CCR7,CCR9,CCR10,CD11c,CD137,CD138,CD14,CD163,CD168,CD 177,CD19,CD20,CD209,CD209L,CD22,CD226,CD248,CD25,CD27,CD274,CD276,CD28,CD30,CD300A,CD33,CD37,CD38,CD4,CD40,CD44,CD45,CD46,CD47,CD48,CD5,CD52,CD55,CD56,CD59,CD62E,CD68,CD69,CD70,CD74,CD79a,CD79b,CD8,CD80,CD86,CD90.2,CD96,CLEC12A,CLEC12B,CLEC7A,CLEC9A,CR1,CR3,CRTAM,CSF1R,CTLA4,CXCR1/2,CXCR4,CXCR5,DDR1,DDR2,DEC-205,DLL4,DR6,FAP,FCamR,FCMR,FcR’s,Fire,GITR,HHLA2,II型HLA(HLA class II),HVEM,ICOSLG,IFNAR,IFNLR1,IL10R1,IL10R2,IL12R,IL13RA1,IL13RA2,IL15R,IL17RA,IL17RB,IL17RC,IL17RE,IL20R1,IL20R2,IL21R,IL22R1,IL22RA,IL23R,IL27R,IL29R,IL2Rg,IL31R,IL36R,IL3RA,IL4R,IL6R,IL5R,IL7R,IL9R,整合素(Integrins),LAG3,LIFR,MAG/Siglec-4(唾液酸结合性免疫球蛋白样凝集素-4),MMR,MSR1,NCR3LG1,NKG2D,NKp30,NKp46,OX40(CD134),PDCD1,PROKR1,PVR,PVRIG,PVRL2,PVRL3,RELT,SIGIRR,Siglec-1(唾液酸结合性免疫球蛋白样凝集素-1),Siglec-10,Siglec-5,Siglec-6,Siglec-7,Siglec-8,Siglec-9,SIRPA,SLAMF7,TACI,TCR–列表组分/assoc(TCR-listcomponents/assoc),PTCRA,TCRb,CD3z,CD3,TEK,TGFBR1,TGFBR2,TGFBR3,TIGIT,TLR2,TLR4,TNFα,TROY,TSLPR,TYRO,VLDLR,VSIG4,IL2R-y和VTCN1。
- 根据权利要求158所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G3为O。
- 根据权利要求158-159中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G1为氢,R I-G2为氢。
- 根据权利要求158-160中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,L I-1x选自以下组:能够与氨基偶联的基团、能够与巯基偶联的基团和点击化学基团。
- 根据权利要求158-164中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,L I-x还包含L I-2,L I-2为权利要求60-149中任一项所述的L I-2。
- 根据权利要求158-165中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,L I-x还包含L I-3,L I-3为权利要求132-149中任一项所述的L I-3。
- 根据权利要求167所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G3为O。
- 根据权利要求167-168中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,R I-G1为氢,R I-G2为氢。
- 一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中,所述化合物包含选自以下组的结构:其中,R I-p选自以下组:H,-CH 3、-CH-(CH 3) 2、-CH 2-CH(CH 3) 2、-CH(CH 3)-CH 2-CH 3、-CH 2-C 6H 5、-C 8NH 6、-CH 2-C 6H 4-OH、-CH 2-COOH、-CH 2-CONH 2、-(CH 2) 2-COOH、-(CH 2) 4-NH 2、-(CH 2) 2-CONH 2、-(CH 2) 2-S-CH 3、-CH 2-OH、-CH(CH 3)-OH、-CH 2-SH、-C 3H 6、-CH 2-C 3H 3N、-(CH 2) 3-NHC(NH)NH 2和-(CH 2) 3-NHCONH 2。
- 制备权利要求1-170中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的方法,其包含以下步骤:在适于在配体和化合物之间形成键的条件下,使所述配体与权利要求158-166中任一项所述的化合物接触。
- 一种药物组合物,其含有权利要求1-170中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,以及任选地药学上可接受的载体。
- 一种影响免疫系统功能的方法,包括向受试者施用权利要求1-170中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,或权利要求172所述的药物组合物。
- 根据权利要求173所述的方法,所述影响免疫系统功能包含影响免疫细胞的功能。
- 根据权利要求173-174中任一项所述的方法,所述免疫细胞选自以下组:颗粒白细胞和无颗粒白细胞。
- 根据权利要求173-175中任一项所述的方法,所述免疫细胞选自以下组:中性粒细胞、嗜酸性粒细胞、和嗜碱性粒细胞。
- 根据权利要求173-175中任一项所述的方法,所述免疫细胞选自以下组:淋巴细胞和吞噬细胞。
- 根据权利要求173-175中任一项所述的方法,所述免疫细胞选自以下组:B细胞、T细胞、自然杀伤细胞、单核细胞、巨噬细胞、肥大细胞和树突状细胞。
- 权利要求1-170中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐和/或权利要求172所述的药物组合物在制备药物中的应用,所述药物用于预防和/或治疗疾病和/或症状。
- 根据权利要求179所述的用途,所述疾病和/或症状包含与糖皮质激素受体信号转导相关的疾病和/或症状。
- 根据权利要求179-180中任一项所述的用途,所述疾病和/或症状选自以下组:增生性疾病和/或症状、代谢性疾病和/或症状、炎症疾病和/或症状和神经退行性疾病和/或症状。
- 根据权利要求179-181中任一项所述的用途,所述疾病和/或症状选自以下组:系统性自身免疫疾病和/或症状、血液系统相关疾病和/或症状、神经肌肉系统相关疾病和/或症状、消化系统相关疾病和/或症状、泌尿系统相关疾病和/或症状、内分泌腺系统相关疾病和/或症状、皮肤肌肉系统相关疾病和/或症状、和呼吸系统系统相关疾病和/或症状。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:类风湿关节炎、系统性红斑狼疮、硬皮病、干燥综合症、强直性脊柱炎、韦格纳肉芽肿病和系统性硬化。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:自身免疫性溶血性贫血、恶性贫血、特发性血小板减少性紫癜、特发性血小板减少症和血管炎。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:多发性硬化、重症肌无力和古兰巴雷综症。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:溃疡性结肠炎、克隆恩病、自身免疫性肝病和萎缩性胃炎。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:IgA肾病、原发性肾病综合征、自身免疫性肾小球肾炎、肺肾出血综合征和狼疮肾炎。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:I型糖尿病、Grave's病、桥本甲状腺炎、原发性肾上腺皮质萎缩和慢性甲状腺炎。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状选自以下组:银屑病、寻常型天孢疹、皮肤红斑狼疮、皮肌炎和风湿性多肌痛。
- 根据权利要求179-182中任一项所述的用途,所述疾病和/或症状为哮喘。
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